Pyrrolo-triazine aniline compounds useful as kinase inhibitors

ABSTRACT

Compounds having the formula (I), 
                         
and pharmaceutically acceptable salts, prodrugs, and solvates thereof, are useful as kinase inhibitors, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Z are as described in the specification.

This application is a divisional of U.S. Ser. No. 10/420,399, filed Apr.22, 2003, now U.S. Pat. No. 7,160,883, which claims priority to U.S.Provisional Application Ser. No. 60/374,938, filed Apr. 23, 2002, theentirety of which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to pyrrolotriazine compounds, more particularly,to cycloalkyl, heterocyclo and heteroaryl pyrrolotriazine anilinecompounds useful for treating p38 kinase-associated conditions. Theinvention further pertains to pharmaceutical compositions containing atleast one compound according to the invention useful for treating p38kinase-associated conditions and methods of inhibiting the activity ofp38 kinase in a mammal.

BACKGROUND OF THE INVENTION

A large number of cytokines participate in the inflammatory response,including IL-1, IL-6, IL-8 and TNF-α. Overproduction of cytokines suchas IL-1 and TNF-α: are implicated in a wide variety of diseases,including inflammatory bowel disease, rheumatoid arthritis, psoriasis,multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease,and congestive heart failure, among others [Henry et al., Drugs Fut.,24:1345-1354 (1999); Salituro et al., Curr. Med Chem., 6:807-823(1999)]. Evidence in human patients indicates that protein antagonistsof cytokines are effective in treating chronic inflammatory diseases,such as, for example, monoclonal antibody to TNF-α: (Enbrel) [Rankin etal., Br. J Rheumatol., 34:334-342 (1995)], and soluble TNF-α receptor-Fcfusion protein (Etanercept) [Moreland et al., Ann. Intern. Med,130:478-486 (1999)].

The biosynthesis of TNF-α occurs in many cell types in response to anexternal stimulus, such as, for example, a mitogen, an infectiousorganism, or trauma. Important mediators of TNF-α production are themitogen-activated protein (MAP) kinases, and in particular, p38 kinase.These kinases are activated in response to various stress stimuli,including but not limited to proinflammatory cytokines, endotoxin,ultraviolet light, and osmotic shock. Activation of p38 requires dualphosphorylation by upstream MAP kinase kinases (MKK3 and MKK6) onthreonine and tyrosine within a Thr-Gly-Tyr motif characteristic of p38isozymes.

There are four known isoforms of p38, i.e., p38-α, p38β, p38γ, and p38δ.The α and β isoforms are expressed in inflammatory cells and are keymediators of TNF-α production. Inhibiting the p38α and β enzymes incells results in reduced levels of TNF-α expression. Also, administeringp38α and β inhibitors in animal models of inflammatory disease hasproven that such inhibitors are effective in treating those diseases.Accordingly, the p38 enzymes serve an important role in inflammatoryprocesses mediated by IL- 1 and TNF-α. Compounds that reportedly inhibitp38 kinase and cytokines such as IL-1 and TNF-α for use in treatinginflammatory diseases are disclosed in U.S. Pat. Nos. 6,277,989 and6,130,235 to Scios, Inc; U.S. Pat. Nos. 6,147,080 and 5,945,418 toVertex Pharmaceuticals Inc; U.S. Pat. Nos. 6,251,914, 5,977,103 and5,658,903 to Smith-Kline Beecham Corp.; U.S. Pat. Nos. 5,932,576 and6,087,496 to G.D. Searle & Co.; WO 00/56738 and WO 01/27089 to AstraZeneca; WO 01/34605 to Johnson & Johnson; WO 00/12497 (quinazolinederivatives as p38 kinase inhibitors); WO 00/56738 (pyridine andpyrimidine derivatives for the same purpose); WO 00/12497 (discusses therelationship between p38 kinase inhibitors); and WO 00/12074 (piperazineand piperidine compounds useful as p38 inhibitors).

The present invention provides certain pyrrolotriazine compounds,particularly, pyrrolotriazine aniline compounds useful as kinaseinhibitors, particularly kinases p38α and β. Pyrrolotriazine compoundsuseful as tyrosine kinase inhibitors are disclosed in U.S. Pat. No.6,982,265 assigned to the present assignee. Methods of treating p38kinase-associated conditions as well as pyrrolotriazine compounds usefulfor that purpose are described in U.S. Pat. No. 6,670,357, assigned tothe present assignee and having common inventors herewith.Pyrrolotriazine compounds substituted with an acidic group reportedlyhaving sPLA₂-inhibitory activity are disclosed in WO 01/14378 A1 toShionogi & Co., Ltd, published Mar. 1, 2001 in Japanese. Each of thepatent applications, patents, and publications referred to herein isincorporated herein by reference.

SUMMARY OF THE INVENTION

The instant invention pertains to compounds of formula (I),

enantiomers, diastereomers, salts, and solvates thereof, wherein:

-   -   X is selected from —O—, —OC(═O)—, —S—, —S(═O)—, —SO₂—, —C(═O)—,        —CO₂—, —NR₈—, —NR₈C(═O)—, —NR₈C(═O)NR₉—, —NR₈CO₂—, —NR₈SO₂—,        —NR₈SO₂NR₉—, —SO₂NR₈—, —C(═O)NR₈—, halogen, nitro, and cyano, or        X is absent;    -   Z is —C(═O)NR₁₀—B^(b), —(CH₂)—C(═O)NR₁₀—B^(c),        —NR_(10a)C(═O)—B^(a), —(CH₂)—NR_(10a)C(═O)—B^(c),        —NR_(10a)C(═O)NR₁₀—B, —NR₁₀SO₂—B, —SO₂NR₁₀—B, —C(═O)—B^(a),        —CO₂—B^(e), —OC(═O)—B^(a), —C(═O)NR_(10a)—NR_(10a)—B^(d),        —NR₁₀CO₂—B^(a) or —C(═O)NR₁₀—(CH₂)C(═O)B^(a);    -   B is        -   (a) optionally-substituted cycloalkyl,            optionally-substituted heterocyclo, or optionally            substituted heteroaryl; or        -   (b) aryl substituted with one R₁₁ and zero to two R₁₂;    -   B^(a) is optionally substituted alkyl, optionally-substituted        cycloalkyl, optionally-substituted heterocyclo, optionally        substituted aryl, or optionally substituted heteroaryl;    -   B^(b) is        -   (a) optionally-substituted cycloalkyl ,            optionally-substituted heterocyclo, or optionally            substituted heteroaryl;        -   (b) aryl substituted with one R₁₁ and zero to two R₁₂; or        -   (c) —C(═O)R₁₃, —CO₂R₁₃, —C(═O)NR₁₃R_(13a);    -   B^(c) is optionally substituted alkyl, optionally substituted        alkoxy, optionally-substituted cycloalkyl,        optionally-substituted heterocyclo, optionally substituted aryl,        or optionally substituted heteroaryl;    -   B^(d) is hydrogen, —C(═O)R₁₃, or —CO₂R₁₃;    -   B^(e) is hydrogen, optionally substituted alkyl,        optionally-substituted cycloalkyl, optionally-substituted        heterocyclo, optionally substituted aryl, or optionally        substituted heteroaryl;    -   R₁ and R₅ are independently selected from hydrogen, alkyl,        substituted alkyl, —OR₁₄, —SR₁₄, —OC(═O)R₁₄, —CO₂R₁₄,        —C(═O)NR₁₄R_(14a), —NR₁₄R_(14a), —S(═O)R₁₄, —SO₂R₁₄,        —SO₂NR₁₄R_(14a), —NR₁₄SO₂NR_(14a)R_(14b), —NR_(14a)SO₂R₁₄,        —NR₁₄C(═O)R_(14a), —NR₁₄CO₂R_(14a), —NR₁₄C(═O)NR_(14a)R_(14b),        halogen, nitro, and cyano;    -   R₂ is hydrogen or C₁₋₄alkyl;    -   R₃ is hydrogen, methyl, perfluoromethyl, methoxy, halogen,        cyano, NH₂, or NH(CH₃);    -   R₄ is selected from:        -   (a) hydrogen, provided that R₄ is not hydrogen if X is            —S(═O)—, —SO₂—, —NR₈CO₂—, or —NR₈SO₂—;        -   (b) alkyl, alkenyl, and alkynyl optionally independently            substituted with keto and/or one to four R₁₇;        -   (c) aryl and heteroaryl either of which may be optionally            independently substituted with one to three R₁₆; and        -   (d) heterocyclo and cycloalkyl either of which may be            optionally independently substituted with keto and/or one to            three R₁₆; or        -   (e) R₄ is absent if X is halogen, nitro, or cyano;    -   R₆ is attached to any available carbon atom of phenyl ring A and        at each occurrence is independently selected from alkyl,        halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy,        alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano,        carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono,        arylthiono, arylsulfonylamine, alkylsulfonylamine, sulfonic        acid, alkysulfonyl, sulfonamido, phenyl, benzyl, aryloxy, and        benzyloxy, wherein each R₆ group in turn may be further        substituted by one to two R₁₈;    -   R₈ and R₉ are independently selected from hydrogen, alkyl,        substituted alkyl, aryl, cycloalkyl, heterocyclo, and        heteroaryl;    -   R₁₀ and R_(10a) are independently selected from hydrogen, alkyl,        substituted alkyl, alkoxy, and aryl;    -   R₁₁ is selected from        -   (a) alkyl, haloalkyl, alkoxy, haloalkoxy, —SO₂alkyl,            cycloalkyl, heterocyclo, and heteroaryl any of which may be            optionally subsituted; or        -   (b) halo, cyano, amino, alkylamino, and dialkylamino;    -   R₁₂ is selected from alkyl, R₁₇, and C₁₋₄alkyl substituted with        keto (═O) and/or one to three R₁₇;    -   R₁₃ and R_(13a) are independently selected from hydrogen,        optionally substituted alkyl, optionally substituted cycloalkyl        and optionally subsituted aryl;    -   R₁₄, R_(14a) and R_(14b) are independently selected from        hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl,        heterocyclo, and heteroaryl, except when R₁₄ is joined to a        sulphonyl group as in —S(═O)R₁₄, —SO₂R₁₄, and —NR_(14a)SO₂R₁₄,        then R₁₄ is not hydrogen;    -   R₁₆ is selected from alkyl, R₁₇, and C₁₋₄alkyl substituted with        keto (═O) and/or one to three R₁₇;    -   R₁₇ is selected from        -   (a) halogen, haloalkyl, haloalkoxy, nitro, cyano, —SR₂₃,            —OR₂₃, —NR₂₃R₂₄, —NR₂₃SO₂R₂₅, —SO₂R₂₅, —SO₂NR₂₃R₂₄, —CO₂R₂₃,            —C(═O)R₂₃, —C(═O)NR₂₃R₂₄, —OC(═O)R₂₃, —OC(═O)NR₂₃R₂₄,            —NR₂₃C(═O)R₂₄, —NR₂₃CO₂R₂₄;        -   (b) aryl or heteroaryl either of which may be optionally            substituted with one to three R₂₆; or        -   (c) cycloalkyl or heterocyclo optionally substituted with            keto(═O) and/or one to three R₂₆;    -   R₁₈ and R₂₆ are independently selected from C₁₋₆alkyl,        C₂₋₆alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro,        amino, C₁₋₄alkylamino, aminoC₁₋₄alkyl, hydroxy,        hydroxyC₁₋₄alkyl, alkoxy, C₁₋₄alkylthio, aryl, heterocyclo,        (aryl)alkyl, aryloxy, and (aryl)alkoxy;    -   R₂₃ and R₂₄ are each independently selected from hydrogen,        alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl,        cycloalkyl, heteroaryl, and heterocyclo;    -   R₂₅ is selected from alkyl, substituted alkyl, aryl, heteroaryl,        cycloalkyl and heterocyclo; and    -   m is 0, 1, 2 or 3.

The invention further pertains to pharmaceutical compositions containingcompounds of formula (I), and to methods of treating conditionsassociated with the activity of p38 kinase (α and β), comprisingadministering to a mammal a pharmaceutically-acceptable amount of acompound of formula (I).

DESCRIPTION OF THE INVENTION

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification, unless otherwise limited in specificinstances, either individually or as part of a larger group.

The term “alkyl” refers to straight or branched chain unsubstitutedhydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbonatoms. The expression “lower alkyl” refers to unsubstituted alkyl groupsof 1 to 4 carbon atoms. When a subscript is used with reference to analkyl or other group, the subscript refers to the number of carbon atomsthat the group may contain. For example, the term “C₀₋₄alkyl” includes abond and alkyl groups of 1 to 4 carbon atoms.

The term “substituted alkyl” refers to an alkyl group substituted by oneto four substituents selected from halogen, hydroxy, alkoxy, keto (═O),alkanoyl, aryloxy, alkanoyloxy, NR_(a)R_(b), alkanoylamino, aroylamino,aralkanoylamino, substituted alkanoylamino, substituted arylamino,substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio,alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl,aralkylsulfonyl, —SO₂NR_(a)R_(b), nitro, cyano, —CO₂H, —CONR_(a)R_(b),alkoxycarbonyl, aryl, guanidino and heteroaryls or heterocyclos (such asindolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,pyrimidyl and the like), wherein R_(a) and R_(b) are selected fromhydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, heterocycle, and heterocyclealkyl. The substituent onthe alkyl optionally in turn may be further substituted, in which caseit will be with substituted one or more of C₁₋₄alkyl, C₂₋₄alkenyl,halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C₁₋₄alkylamino,aminoC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄alkyl, alkoxy, alkylthio, phenyl,benzyl, phenyloxy, and/or benzyloxy.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, andmost preferably 2 to 8 carbon atoms, having at least one double bond,and depending on the number of carbon atoms, up to four double bonds.

The term “substituted alkenyl” refers to an alkenyl group substituted byone to two substituents selected from those recited above forsubstituted alkyl groups.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, andmost preferably 2 to 8 carbon atoms, having at least one triple bond,and depending on the number of carbon atoms, up to four triple bonds.

The term “substituted alkynyl” refers to an alkynyl group substituted byone to two substituents selected from those recited above for alkylgroups.

When the term alkyl is used in connection with another group, as inheterocycloalkyl or cycloalkylalkyl, this means the identified (firstnamed) group is bonded directly through an alkyl group which may bebranched or straight chain (e.g., cyclopropylC₁₋₄alkyl means acyclopropyl group bonded through a straight or branched chain alkylgroup having one to four carbon atoms.). In the case of substituents, asin “substituted cycloalkylalkyl,” the alkyl portion of the group,besides being branched or straight chain, may be substituted as recitedabove for substituted alkyl groups and/or the first named group (e.g.,cycloalkyl) may be substituted as recited herein for that group.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “aryl” refers to monocyclic or bicyclic aromatic substituted orunsubstituted hydrocarbon groups having 6 to 12 carbon atoms in the ringportion, such as phenyl, naphthyl, and biphenyl groups. Aryl groups mayoptionally include one to three additional rings (either cycloalkyl,heterocyclo or heteroaryl) fused thereto.

Examples include:

and the like. Each ring of the aryl may be optionally substituted withone to three R_(c) groups, wherein R_(c) at each occurrence is selectedfrom alkyl, substituted alkyl, halogen, trifluoromethoxy,trifluoromethyl, —SR, —OR, —NRR′, —NRSO₂R′, —SO₂R, —SO₂NRR′, —CO₂R′,—C(═O)R′, —C(═O)NRR′, —OC(═O)R′, —OC(═O)NRR′, —NRC(═O)R′, —NRCO₂R′,phenyl, C₃₋₇ cycloalkyl, and five-to-six membered heterocyclo orheteroaryl, wherein each R and R′ is selected from hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, phenyl, C₃₋₇cycloalkyl,and five-to-six membered heterocyclo or heteroaryl, except in the caseof a sulfonyl group, then R is not going to be hydrogen. Eachsubstituent R_(c) optionally in turn may be further substituted by oneor more (preferably 0 to 2) R_(d) groups, wherein R_(d) is selected fromC₁₋₆alkyl, C₂₋₆alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro,amino, C₁₋₄alkylamino, aminoC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄alkyl,alkoxy, alkylthio, phenyl, benzyl, phenylethyl, phenyloxy, andbenzyloxy.

The term “aralkyl” refers to an aryl group bonded directly through analkyl group, such as benzyl, wherein the alkyl group may be branched orstraight chain. In the case of a “substituted aralkyl,” the alkylportion of the group besides being branched or straight chain, may besubstituted as recited above for substituted alkyl groups and/or thearyl portion may be substituted as recited herein for aryl. Thus, theterm “optionally substituted benzyl” refers to the group

wherein each R group may be hydrogen or may also be selected from R_(c)as defined above, in turn optionally substituted with one or more R_(d).At least two of these “R” groups should be hydrogen and preferably atleast five of the “R” groups is hydrogen. A preferred benzyl groupinvolves the alkyl-portion being branched to define

The term “heteroaryl” refers to a substituted or unsubstituted aromaticgroup for example, which is a 4 to 7 membered monocyclic, 7 to 11membered bicyclic, or 10 to 15 membered tricyclic ring system, which hasat least one heteroatom and at least one carbon atom-containing ring.Each ring of the heteroaryl group containing a heteroatom can containone or two oxygen or sulfur atoms and/or from one to four nitrogenatoms, provided that the total number of heteroatoms in each ring isfour or less and each ring has at least one carbon atom. The fused ringscompleting the bicyclic and tricyclic groups may contain only carbonatoms and may be saturated, partially saturated, or unsaturated. Thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenatoms may optionally be quaternized. Heteroaryl groups which arebicyclic or tricyclic must include at least one fully aromatic ring butthe other fused ring or rings may be aromatic or non-aromatic. Theheteroaryl group may be attached at any available nitrogen or carbonatom of any ring. It may optionally be substituted with one to three(preferably 0 to 2) R_(c) groups, as defined above for aryl, which inturn may be substituted with one or more (preferably o to 2) R_(d)groups, also as recited above.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl (i.e.,

), thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl,dihydroisoindolyl, tetrahydroquinolinyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term “cycloalkyl” refers to a saturated or partially unsaturatednon-aromatic cyclic hydrocarbon ring system, preferably containing 1 to3 rings and 3 to 7 carbon atoms per ring, which may be substituted orunsubstituted and/or which may be fused with a C₃-C₇ carbocylic ring, aheterocyclic ring, or which may have a bridge of 3 to 4 carbon atoms.The cycloalkyl groups including any available carbon or nitrogen atomson any fused or bridged rings optionally may have 0 to 3 (preferably0-2) substituents selected from R_(c) groups, as recited above, and/orfrom keto (where appropriate) which in turn may be substituted with oneto three R_(d) groups, also as recited above. Thus, when it is statedthat a carbon-carbon bridge may be optionally substituted, it is meantthat the carbon atoms in the bridged ring optionally may be substitutedwith an R_(c) group, which preferably is seleted from C₁₋₄alkyl,C₂₋₄alkenyl, halogen, haloalkyl, haloalkoxy, cyano, amino,C₁₋₄alkylamino, aminoC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄alkyl, andC₁₋₄alkoxy. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, bicycloheptane, cycloctyl,cyclodecyl, cyclododecyl, and adamantyl.

The terms “heterocycle”, “heterocyclic” and “heterocyclo” each refer toa fully saturated or partially unsaturated nonaromatic cyclic group,which may be substituted or unsubstituted, for example, which is a 4 to7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 memberedtricyclic ring system, which has at least one heteroatom in at least onecarbon atom-containing ring. Each ring of the heterocyclic groupcontaining a heteroatom may have 1, 2 or 3 heteroatoms selected fromnitrogen, oxygen, and sulfur atoms, where the nitrogen and sulfurheteroatoms also optionally may be oxidized and the nitrogen heteroatomsalso optionally may be quaternized. Preferably two adjacent heteroatomsare not simultaneously selected from oxygen and nitrogen. Theheterocyclic group may be attached at any nitrogen or carbon atom. Theheterocyclo groups optionally may have 0 to 3 (preferably 0-2)substituents selected from keto (═O), and/or one or more R_(c) groups,as recited above, which in turn may be substituted with one to threeR_(d) groups, also as recited above.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl,azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,thiiranyl, triazinyl, and triazolyl, and the like.

Exemplary bicyclic hetrocyclic groups include2,3-dihydro-2-oxo-1H-indolyl, benzothiazolyl, benzoxazolyl,benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,1-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl, and the like.

Also included are smaller heterocyclos, such as epoxides and aziridines.

Unless otherwise indicated, when reference is made to aspecifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl),heterocyclo (e.g., pyrrolidinyl) or heteroaryl (e.g., indolyl), thereference is intended to include rings having 0 to 3, preferably 0-2,substituents selected from those recited above for the aryl, cycloalkyl,heterocyclo and/or heteroaryl groups, as appropriate. Additionally, whenreference is made to a specific heteroaryl or heterocyclo group, thereference is intended to include those systems having the maximum numberof non-cumulative double bonds or less than the maximum number of doublebonds. Thus, for example, the term “isoquinoline” refers to isoquinolineand tetrahydroisoquinoline.

Additionally, it should be understood that one skilled in the field maymake appropriate selections for the substituents for the aryl,cycloalkyl, heterocyclo, and heteroaryl groups to provide stablecompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds. Thus, for example, in compoundsof formula (I), when B is a cyclopropyl ring, preferably the ring has nomore than two substituents, and preferably said substituents do notcomprise nitro (NO₂), more than one cyano group, or three halogengroups. Similarly, when m is 3, preferably R₆, the substituents on thephenyl ring A, are not all nitro, and so forth.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

The term “haloalkyl” means an alkyl having one or more halosubstituents.

The term “perfluoromethyl” means a methyl group substituted by one, two,or three fluoro atoms, i.e., CH₂F, CHF₂ and CF₃. The term“perfluoroalkyl” means an alkyl group having from one to five fluoroatoms, such as pentafluoroethyl.

The term “haloalkoxy” means an alkoxy group having one or more halosubstituents. For example, “haloalkoxy” includes —OCF₃.

The term “carbocyclic” means a saturated or unsaturated monocyclic orbicyclic ring in which all atoms of all rings are carbon. Thus, the termincludes cycloalkyl and aryl rings. The carbocyclic ring may besubstituted in which case the substituents are selected from thoserecited above for cycloalkyl and aryl groups.

When the term “unsaturated” is used herein to refer to a ring or group,the ring or group may be fully unsaturated or partially unsaturated.

Definitions for the various other groups that are recited above inconnection with substituted alkyl, substituted alkenyl, aryl,cycloalkyl, and so forth, are as follows: alkoxy is —OR^(e), alkanoyl is—C(═O)R^(e), aryloxy is —OAr, alkanoyloxy is —OC(═O)R^(e), amino is—NH₂, alkylamino is —NHR^(e) or —N(R^(e))₂, arylamino is —NHAr or—NR^(e)Ar, aralkylamino is —NH—R^(f)—Ar, alkanoylamino is—NH—C(═O)R^(e), aroylamino is —NH—C(═O)Ar, aralkanoylamino is—NH—C(═O)R^(f)-Ar, thiol is —SH, alkylthio is —SR^(e), arylthio is —SAr,aralkylthio is —S—R^(f)—Ar, alkylthiono is —S(═O)R^(e), arylthiono is—S(═O)Ar, aralkylthiono is —S(═O)R^(f)—Ar, alkylsulfonyl is—SO_((q))R^(e), arylsulfonyl is —SO_((q))Ar, arylsulfonylamine is—NHSO_((q))Ar, alkylsulfonylamine is —NHSO₂R^(e), aralkylsulfonyl is—SO_((q))R^(f)Ar, sulfonamido is —SO₂NH₂, substituted sulfonamide is—SO₂NHR^(e) or —SO₂N(R^(e))₂, nitro is —NO₂, carboxy is —CO₂H, carbamylis —CONH₂, substituted carbamyl is —C(═O)NHR^(g) or —C(═O)NR^(g)R^(h),alkoxycarbonyl is —C(═O)OR^(e), carboxyalkyl is —R^(f)—CO₂H, sulfonicacid is —SO₃H, guanidino is

and ureido is

wherein R^(e) is alkyl or substituted alkyl as defined above, R^(f) isalkylene or substituted alkylene as defined above, R^(g) and R^(h) areselected from alkyl, substituted alkyl, aryl, aralkyl, cycloalkyl,heterocyclo, and heteraryl; Ar is an aryl as defined above, and q is 2or 3.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds.

The compounds of the present invention may form salts which are alsowithin the scope of this invention. Pharmaceutically acceptable (i e.non-toxic, physiologically acceptable) salts are preferred, althoughother salts are also useful, e.g., in isolating or purifying thecompounds of this invention.

The compounds of the present invention may form salts with alkali metalssuch as sodium, potassium and lithium, with alkaline earth metals suchas calcium and magnesium, with organic bases such as dicyclohexylamine,tributylamine, pyridine and amino acids such as arginine, lysine and thelike. Such salts can be formed as known to those skilled in the art.

The compounds of the present invention may form salts with a variety oforganic and inorganic acids. Such salts include those formed withhydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuricacid, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid,benzenesulfonic acid, toluenesulfonic acid and various others (e.g.,nitrates, phosphates, borates, tartrates, citrates, succinates,benzoates, ascorbates, salicylates and the like). Such salts can beformed as known to those skilled in the art. Salt forms of the compoundsmay be advantageous for improving the compound dissolution rate and oralbioavailability.

In addition, zwitterions (“inner salts”) may be formed.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The definition of compounds according to the invention embraces all thepossible stereoisomers and their mixtures. It embraces the racemic formsand the isolated optical isomers having the specified activity. Theracemic forms can be resolved by physical methods, such as, for example,fractional crystallization, separation or crystallization ofdiastereomeric derivatives or separation by chiral columnchromatography. The individual optical isomers can be obtained from theracemates from the conventional methods, such as, for example, saltformation-with an optically active acid followed by crystallization.

Compounds of the present invention may also have prodrug forms. Anycompound that will be converted in vivo to provide the bioactive agent(i.e., the compound for formula I) is a prodrug within the scope andspirit of the invention.

Various forms of prodrugs are well known in the art. For examples ofsuch prodrug derivatives, see:

-   -   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985)        and Methods in Enzymology, Vol. 112, pp. 309-396, edited by K.        Widder, et al. (Academic Press, 1985);    -   b) A Textbook of Drug Design and Development, edited by        Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and        Application of Prodrugs,” by H. Bundgaard, pp. 113-191 (1991);        and    -   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, pp. 1-38        (1992), each of which is incorporated herein by reference.

It should further be understood that solvates (e.g., hydrates) of thecompounds of Formula (I) are also with the scope of the presentinvention. Methods of solvation are generally known in the art.

Preferred compounds of formula (I) include compounds having thestructure:

Preferred compounds include those having the struture of formula (I*),

enantiomers, diastereomers, salts and solvates thereof, wherein:

-   -   X is selected from —O—, —OC(═O)—, —S—, —S(═O)—, —SO₂—, —C(═O)—,        —CO₂—, —NR₈—, —NR₈C(═O)—, —NR₈C(═O)NR₉—, —NR₈CO₂—, —NR₈SO₂—,        —NR₈SO₂NR₉—, —SO₂NR₈—, —C(═O)NR₈—, halogen, nitro, and cyano, or        X is absent;    -   Y is —C(═O)NR₁₀—, —NR_(10a)C(═O)NR₁₀—, —NR₁₀SO₂—, —SO₂NR₁₀—,        —C(═O)—, —CO₂— or —OC(═O)—;    -   B is optionally-substituted cycloalkyl, heterocyclo, or        heteroaryl; or aryl substituted with one R₁₁ and zero to two        R₁₂; or when Y is —C(═O)NR₁₀—, B also may be selected from        —C(═O)R₁₃, —CO₂R₁₃, —C(═O)NR₁₃R_(13a);    -   R₁ and R₅ are independently selected from hydrogen, alkyl,        substituted alkyl, —OR₁₄, —SR₁₄, —OC(═O)R₁₄, —CO₂R₁₄,        —C(═O)NR₁₄R_(14a), —NR₁₄R_(14a), —S(═O)R₁₄, —SO₂R₁₄,        —SO₂NR₁₄R_(14a), —NR₁₄SO₂NR_(14a)R_(14b), —NR_(14a)SO₂R₁₄,        —NR₁₄C(═O)R_(14a), —NR₁₄CO₂R_(14a), —NR₁₄C(═O)NR_(14a)R_(14b),        halogen, nitro, and cyano;    -   R₂ is hydrogen or C₁₋₄alkyl;    -   R₃ is hydrogen, methyl, perfluoromethyl, methoxy, halogen,        cyano, NH₂, or NH(CH₃);    -   R₄ is selected from:        -   (a) hydrogen, provided that R₄ is not hydrogen if X is            —S(═O)—, —SO₂—, —NR₈CO₂—, or —NR₈SO₂—;        -   (b) alkyl, alkenyl, and alkynyl optionally substituted with            keto and/or one to four R₁₇;        -   (c) aryl and heteroaryl optionally substituted with one to            three R₁₆; and        -   (d) heterocyclo and cycloalkyl optionally substituted with            keto and/or one to three R₁₆; or        -   (e) R₄ is absent if X is halogen, nitro, or cyano;    -   R₆ is attached to any available carbon atom of phenyl ring A and        at each occurrence is independently selected from alkyl,        halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy,        alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano,        carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono,        arylthiono, arylsulfonylamine, alkylsulfonylamine, sulfonic        acid, alkysulfonyl, sulfonamido, phenyl, benzyl, aryloxy, and        benzyloxy, wherein each R₆ group in turn may be further        substituted by one to two R₁₈;    -   R₈ and R₉ are independently selected from hydrogen, alkyl,        substituted alkyl, aryl, cycloalkyl, heterocyclo, and        heteroaryl;    -   R₁₀ and R_(10a) are independently selected from hydrogen, alkyl,        substituted alkyl, alkoxy, and aryl;    -   R₁₁ is selected from optionally-substituted cycloalkyl,        heterocyclo, and heteroaryl;    -   R₁₂ is selected from alkyl, R₁₇, and C₁₋₄alkyl substituted with        keto (═O) and/or one to three R₁₇;    -   R₁₃ and R_(13a) are selected from hydrogen, alkyl, and        substituted alkyl;    -   R₁₄, R_(14a) and R_(14b) are independently selected from        hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl,        heterocyclo, and heteroaryl, except when R₁₄ is joined to a        sulphonyl group as in —S(═O)R₁₄, —SO₂R₁₄, and —NR_(14a)SO₂R₁₄,        then R₁₄ is not hydrogen;    -   R₁₆ is selected from alkyl, R₁₇, and C₁₋₄alkyl substituted with        keto (═O) and/or one to three R₁₇;    -   R₁₇ is selected from halogen, haloalkyl, haloalkoxy, nitro,        cyano, —SR₂₃, —OR₂₃, —NR₂₃R₂₄, —NR₂₃SO₂R₂₅, —SO₂R₂₅,        —SO₂NR₂₃R₂₄, —CO₂R₂₃, —C(═O)R₂₃, —C(═O)NR₂₃R₂₄, —OC(═O)R₂₃,        —OC(═O)NR₂₃R₂₄, —NR₂₃C(═O)R₂₄, —NR₂₃CO₂R₂₄, aryl or heteroaryl        optionally substituted with one to three R₂₆; or cycloalkyl or        heterocyclo optionally substituted with keto (═O) and/or one to        three R₂₆;    -   R₁₈ and R₂₆ are independently selected from C₁₋₆alkyl,        C₂₋₆alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro,        amino, C₁₋₄alkylamino, aminoC₁₋₄alkyl, hydroxy,        hydroxyC₁₋₄alkyl, alkoxy, C₁₋₄alkylthio, phenyl, benzyl,        phenyloxy, and benzyloxy;    -   R₂₃ and R₂₄ are each independently selected from hydrogen,        alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl,        cycloalkyl, heteroaryl, and heterocyclo;    -   R₂₅ is selected from alkyl, substituted alkyl, aryl, heteroaryl,        cycloalkyl and heterocyclo; and    -   m is 0, 1, 2 or 3.

Preferred compounds of formula (I*) are those having formula (Ia),

and pharmaceutically-acceptable salts, prodrugs, and solvates thereof,wherein:

-   -   R₃ is methyl, —CF₃, or —OCF₃;.    -   X is —C(═O)—, —NR₈C(═O)—, or —C(═O)NR₈—, wherein R₈ is hydrogen        or C₁₋₄alkyl;    -   Y is —C(═O)NH—, —NHC(═O)NH—, —NHC(═O)— or —NHSO₂—;    -   B is an optionally-substituted monocyclic or bicyclic        cycloalkyl, heteroaryl, or heterocycle, aryl substituted with at        least one R₁₁ and zero to two R₁₂, or when Y is —C(═O)NH—, B        also may be selected from —C(═O)R₁₃, —CO₂R₁₃, and        —C(═O)NR₁₃R_(13a);    -   R₄ is hydrogen, C₂₋₆alkyl, C₁₋₄alkyl optionally substituted with        one to three R₁₇, aryl or heteroaryl optionally substituted with        one to three R₁₆, or cycloalkyl or heterocycle        optionally-substituted with keto (═O) and/or one to three R₁₆;    -   R_(6a) and R_(6b) are independently selected from hydrogen,        C₁₋₆alkyl, substituted C₁₋₄alkyl, halogen, trifluoromethoxy,        trifluoromethyl, —OR₂₇, —C(═O)alkyl, —OC(═O)alkyl, —NR₂₇R₂₈,        —SR₂₇, —NO₂, —CN, —CO₂R₂₇, —CONH₂, —SO₃H, —S(═O)alkyl,        —S(═O)aryl, —NHSO₂-aryl-R₂₇, —SO₂NHR₂₇, —CONHR₂₇, and        —NHC(═O)NHR₂₇;    -   R₁₁ is cycloalkyl, heterocyclo, or heteroaryl optionally        substituted with one to two R₁₆;    -   R₁₃ and R_(13a) are hydrogen, alkyl or substituted alkyl;    -   R₁₂ and R₁₆ are independently selected from C₁₋₄alkyl, R₁₇, and        C₁₋₄alkyl substituted with keto and/or one to two R₁₇;    -   R₁₇ is selected from halogen, hydroxy, C₁₋₄alkoxy,        trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl,        phenyloxy, benzyloxy, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,        C₃₋₇cycloalkyl, and five or six membered heteroaryl or        heterocycle; and    -   R₂₇ and R₂₈ are selected from hydrogen, C₁₋₄alkyl, phenyl,        C₃₋₇cycloalkyl, and five-to-six membered heterocyclo or        heteroaryl.

More preferred are compounds having the formula (Ia), as recited above,wherein:

-   -   R₃ is methyl, —CF₃, or —OCF₃;    -   X is —C(═O)—, —C(═O)NH— or —C(═O)N(C₁₋₄alkyl)-;    -   Y is —C(═O)NH—;    -   B is a C₃₋₇cycloalkyl optionally substituted with one to two R₇,        a five membered heteroaryl optionally substituted with one to        two R₇, a five or six membered heterocyclo optionally        substituted with one to two R₇, aryl substituted with at least        one R₁₁ and optionally substituted with zero to two R₁₂, or when        Y is —C(═O)NH—, B may also be selected from —C(═O)(alkyl),        —CO₂(alkyl), and —C(═O)NH(alkyl);    -   R₄ is hydrogen, C₂₋₆alkyl, C₁₋₄alkyl optionally substituted with        one to three R₁₇, aryl or heteroaryl optionally substituted with        one to three R₁₆, or cycloalkyl or heterocycle        optionally-substituted with keto (═O), and/or one to three R₁₆;    -   R_(6a) and R_(6b) are independently selected from hydrogen,        C₁₋₄alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy,        C₁₋₄alkoxy, cyano, NH₂, NH(C₁₋₄alkyl), and N(C₁₋₄alkyl)₂;    -   R₇ is selected from C₁₋₆alkyl, substituted C₁₋₄alkyl, halogen,        trifluoromethoxy, trifluoromethyl, cyano, —SR₂₀, —OR₂₀,        —NR₂₀R₂₁, —NR₂₀SO₂R₂₁, —SO₂R₁₉, —SO₂NR₂₀R₂₁, —CO₂R₂₀, —C(═O)R₂₀,        —C(═O)NR₂₀R₂₁, —OC(═O)R₂₀, —OC(═O)NR₂₀R₂₁, —NR₂₀C(═O)R₂₁,        —NR₂₀CO₂R₂₁, phenyl, benzyl, C₃₋₇ cycloalkyl, and five-to-six        membered heterocyclo or heteroaryl;    -   R₁₁ is cycloalkyl, heterocyclo, or heteroaryl optionally        substituted with one to two R₁₆;    -   R₁₃ and R_(13a) are hydrogen, alkyl or substituted alkyl;    -   R₁₂ and R₁₆ are independently selected from C₁₋₄alkyl, R₁₇, and        C₁₋₄alkyl substituted with keto and/or one to two R₁₇;    -   R₁₇ is selected from halogen, hydroxy, C₁₋₄alkoxy,        trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl,        phenyloxy, benzyloxy, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,        cyclopentyl, cyclohexyl, or five or six membered heteroaryl or        heterocycle;    -   R₁₉ is C₁₋₄alkyl, phenyl, C₃₋₇cycloalkyl, or five-to-six        membered heterocyclo or heteroaryl;    -   R₂₀ and R₂₁, are selected from hydrogen, C₁₋₄alkyl, phenyl,        C₃₋₇cycloalkyl, and five-to-six membered heterocyclo or        heteroaryl; and    -   R₂₇ and R₂₈ are selected from hydrogen, C₁₋₄alkyl, phenyl,        C₃₋₇cycloalkyl, and five-to-six membered heterocyclo or        heteroaryl.

In compounds of formula (I), preferably R₃ is methyl, —CF₃, or —OCF₃,more preferably methyl; X preferably is —C(═O)— or —C(═O)NH—; and Y ispreferably —C(═O)NH—. Preferably when X is —C(═O)NH—, R₄ is C₂₋₆alkyl orsubstituted C₁₋₄alkyl, more preferably C₁₋₄alkyl oroptionally-substituted benzyl. When X is —C(═O)—, preferably R₄ is anoptionally-substituted aryl or heteroaryl.

When R₄ is a heterocyclo, advantageously it is selected from diazepinyl,morpholinyl, piperidinyl, and pyrrolidinyl, said heterocycle beingoptionally substituted with one to two of C₁₋₄alkyl, hydroxy,C₁₋₄alkoxy, phenyl, and/or benzyl. When X is —C(═O)— and R₄ is aryl orheteroaryl, preferably R₄ is phenyl, pyridinyl, pyrimidinyl, orpyrazinyl, optionally-substituted with C₁₋₄alkyl, halogen, hydroxy,C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl,benzyl, phenyloxy, benzyloxy, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,cyclopentyl, cyclohexyl, or five or six membered heteroaryl orheterocycle.

In compounds of formula (I), preferably phenyl ring A is unsubstitutedor has one substituent. Said optional substituent R_(6a) or R_(6b) ispreferably selected from C₁₋₄alkyl, halogen, trifluoromethoxy,trifluoromethyl, hydroxy, C₁₋₄alkoxy, nitro, and cyano, more preferablythe substituent is R_(6a) and is methyl or ethyl.

In compounds of formula (I), preferably ring B is a cycloalkyl,heteroaryl, or heterocyclo ring selected from:

wherein E, G, J and K are selected from O, S, NH and CH₂, provided thatwhen q is 0, then J and K are not simultaneously selected from O and S;and M is N or CH; wherein each hydrogen atom of E, G, J, K and M mayoptionally be replaced with an R₇ group;

-   -   R₇ is selected from C₁₋₆alkyl, substituted C₁₋₄alkyl, halogen,        trifluoromethoxy, trifluoromethyl, hydroxy, —C₁₋₄alkoxy,        —C(═O)alkyl, —OC(═O)alkyl, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,        —CN, —CO₂alkyl, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, phenyl, benzyl,        C₃₋₇ cycloalkyl, and five-to-six membered heterocyclo or        heteroaryl;    -   n is 0, 1 or 2; and    -   p and q are selected from 0, 1, 2, 3 or 4, provided that p and q        taken together are not greater than 4.

In compounds of formula (I), also preferred are compounds where ring Bis cyclopropyl, oxazolyl, or isoxazolyl which is unsubstituted or hasone substituent R₇ Said substituent R₇ preferably is selected fromC₁₋₆alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy,—C₁₋₄alkoxy, —C(═O)alkyl, —OC(═O)alkyl, NH₂, NH(C₁₋₄alkyl),N(C₁₋₄alkyl)₂, —CN, —CO₂alkyl, —CONH₂, phenyl, benzyl, C₃₋₇ cycloalkyl,and five-to-six membered heterocyclo or heteroaryl, or a C₁₋₄alkylsubstituted with hydroxy, amino, alkylamino, halogen, trifluoromethyl,trifluoromethoxy, or cyano. More preferably R₇ is not present or is—C₁₋₄alkoxy.

Also preferred compounds are those of formula (2a) and (2b),

and pharmaceutically acceptable salts, prodrugs, and solvates thereof,wherein:

-   -   R₃ is methyl or CF₃;    -   B is phenyl having at least one R₁₁ substituent and zero to two        R₁₂ substituents, or B may be selected from:

wherein E, G, J and K are selected from O, S, NH and CH₂, provided thatwhen q is 0, then J and K are not simultaneously selected from O and S;and M is N or CH; wherein each hydrogen atom of E, G, J, K and Moptionally may be replaced with an R₇ group;

-   -   R_(4a) is phenyl or five or six membered heteraryl optionally        substituted with up to two R₁₆;    -   R_(4b) is straight or branched C₂₋₆alkyl; cycloalkyl optionally        substituted with keto and/or up to two R₁₆; heterocycle        optionally substituted with keto and/or up to two R₁₆; or        C₁₋₄alkyl substituted with up to three of halogen,        trifluoromethyl, cyano, hydroxy, alkoxy, haloalkyl, haloalkoxy,        nitro, phenyl, phenyloxy or benzyloxy, wherein said phenyl group        in turn is optionally substituted with one to two R₂₆;    -   R_(6a) is lower alkyl, halogen, trifluoromethoxy,        trifluoromethyl, hydroxy, C₁₋₄alkoxy, nitro, amino,        C₁₋₄alkylalmino, or cyano;    -   R₇ is C₁₋₄alkyl, trifluoromethyl, trifluoromethoxy, halogen,        cyano, nitro, amino, C₁₋₄alkylalmino, hydroxy, C₁₋₄alkoxy,        phenyl, benzyl, phenyloxy, or benzyloxy;    -   R₁₁ is cycloalkyl, heterocyclo, or heteroaryl optionally        substituted with one to two R₁₆;    -   R₁₂ and R₁₆ at each occurrence are independently selected from        hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen,        cyano, nitro, amino, C₁₋₄alkylalmino, hydroxy, alkoxy, phenyl,        benzyl, phenyloxy, and benzyloxy;    -   R₂₆ is selected from C₁₋₄alkyl, trifluoromethyl,        trifluoromethoxy, halogen, cyano, amino, C₁₋₄alkylalmino,        hydroxy, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy;    -   n is 0, 1 or 2; and    -   p and q are 0, 1, 2, 3, or 4, provided that p and q taken        together are not greater than 4.

Most preferred are compounds of formula (2a) or (2b), referenced above,and pharmaceutically acceptable salts, prodrugs, and solvates thereof,wherein:

-   -   R₃ is methyl;    -   B is selected from        -   (a) cyclopropyl or cyclobutyl optionally substituted with            one to two R₇;        -   (b) phenyl substituted with five or six membered heterocyclo            and zero to two R₁₂, or        -   (c) B is selected from one of:

-   -   R_(4a) is phenyl or pyridyl optionally substituted with up to        two R₁₆, as defined above;    -   R_(4b) is straight or branched C₂₋₆alkyl or        optionally-substituted benzyl;    -   R_(6a) is methyl, ethyl, halogen, trifluoromethoxy,        trifluoromethyl, hydroxy, methoxy, ethoxy, or cyano;    -   R₇, R₁₂ and R₁₆ are selected from C₁₋₄alkyl, trifluoromethyl,        trifluoromethoxy, halogen, cyano, nitro, amino, C₁₋₄alkylamino,        aminoC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄alkyl, haloC₁₋₄alkyl,        C₁₋₄alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; and    -   n is 0 or 1.

Utility

The compounds of the invention are selective inhibitors of p38 kinaseactivity, and in particular, isoforms p38α and p38β. Accordingly,compounds of formula (I) have utility in treating conditions associatedwith p38 kinase activity. Such conditions include diseases in whichcytokine levels are modulated as a consequence of intracellularsignaling via p38, and in particular, diseases that are associated withan overproduction of cytokines IL-1, IL-4, IL-8, and TNF-α. As usedherein, the terms “treating” or “treatment” encompass either or bothresponsive and prophylaxis measures, e.g., measures designed to inhibitor delay the onset of the disease or disorder, achieve a full or partialreduction of the symptoms or disease state, and/or to alleviate,ameliorate, lessen, or cure the disease or disorder and/or its symptoms.When reference is made herein to inhibition of “p-38α/β kinase,” thismeans that either p38α and/or p38β kinase are inhibited. Thus, referenceto an IC₅₀ value for inhibiting p-38α/β kinase means that the compoundhas such effectiveness for inhibiting at least one of, or both of, p38αand p38β kinases.

In view of their activity as inhibitors of p-38α/β kinase, compounds ofFormula (I) are useful in treating p-38 associated conditions including,but not limited to, inflammatory diseases, autoimmune diseases,destructive bone disorders, proliferative disorders, angiogenicdisorders, infectious diseases, neurodegenerative diseases, and viraldiseases.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic β-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoisosis, bone resorptiondisease, allograft rejections, fever and myalgias due to infection,cachexia secondary to infection, meloid formation, scar tissueformation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis and multiple myeloma-related bone disorder, acutemyelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma,Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, andShigellosis; Alzheimer's disease, Parkinson's disease, cerebralischemias or neurodegenerative disease caused by traumatic injury;angiogenic disorders including solid tumors, ocular neovasculization,and infantile haemangiomas; viral diseases including acute hepatitisinfection (including hepatitis A, hepatitis B and hepatitis C), HIVinfection and CMV retinitis, AIDS, ARC or malignancy, and herpes;stroke, myocardial ischemia, ischemia in stroke heart attacks, organhyposia, vascular hyperplasia, cardiac and renal reperfusion injury,thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation,endotoxemia and/or toxic shock syndrome, and conditions associated withprostaglandin endoperoxidase syndase-2.

In addition, p38 inhibitors of this invention inhibit the expression ofinducible pro-inflammatory proteins such as prostaglandin endoperoxidesynthase-2 (PGHS-2), also referred to as cyclooxygenase-2 (COX-2).Accordingly, additional p38-associated conditions include edema,analgesia, fever and pain, such as neuromuscular pain, headache, paincaused by cancer, dental pain and arthritis pain. The inventivecompounds also may be used to treat veterinary viral infections, such aslentivirus infections, including, but not limited to equine infectiousanemia virus; or retro virus infections, including felineimmunodeficiency virus, bovine immunodeficiency virus, and canineimmunodeficiency virus.

When the terms “p38 associated condition” or “p38 associated disease ordisorder” are used herein, each is intended to encompass all of theconditions identified above as if repeated at length, as well as anyother condition that is affected by p38 kinase activity.

The present invention thus provides methods for treating suchconditions, comprising administering to a subject in need thereof aneffective amount of at least one compound of Formula (I) or a saltthereof. The methods of treating p38 kinase-associated conditions maycomprise administering compounds of Formula (I) alone or in combinationwith each other and/or other suitable therapeutic agents useful intreating such conditions. Exemplary of such other therapeutic agentsinclude corticosteroids, rolipram, calphostin, CSAIDs, 4-substitutedimidazo [1,2-A]quinoxalines as disclosed in U.S. Pat. No. 4,200,750;Interleukin-10, glucocorticoids, salicylates, nitric oxide, and otherimmunosuppressants; nuclear translocation inhibitors, such asdeoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs)such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisoneor dexamethasone; antiviral agents such as abacavir; antiproliferativeagents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf);cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-αinhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor,and rapamycin (sirolimus or Rapamune) or derivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds.

The present invention also provides pharmaceutical compositions capableof treating p38-kinase associated conditions, including TNF-α, IL-1,and/or IL-8 mediated conditions, as described above. The inventivecompositions may contain other therapeutic agents as described above andmay be formulated, for example, by employing conventional solid orliquid vehicles or diluents, as well as pharmaceutical additives of atype appropriate to the mode of desired administration (e.g.,excipients, binders, preservatives, stabilizers, flavors, etc.)according to techniques such as those well known in the art ofpharmaceutical formulation.

The compounds of Formula (I) may be administered by any means suitablefor the condition to be treated, which may depend on the need forsite-specific treatment or quantity of drug to be delivered. Topicaladministration is generally preferred for skin-related diseases, andsystematic treatment preferred for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds may be delivered orally, such as in the form oftablets, capsules, granules, powders, or liquid formulations includingsyrups; topically, such as in the form of solutions, suspensions, gelsor ointments; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular or intrasternal injection orinfusion techniques (e.g., as sterile injectable aq. or non-aq.solutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; rectally such asin the form of suppositories; or liposomally. Dosage unit formulationscontaining non-toxic, pharmaceutically acceptable vehicles or diluentsmay be administered. The compounds may be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps.

Exemplary compositions for topical administration include a topicalcarrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The inventive compounds may also be orally delivered bysublingual and/or buccal administration, e.g., with molded, compressed,or freeze-dried tablets. Exemplary compositions may includefast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG); an excipient to aid mucosal adhesion such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodiumcarboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,GANTREZ®); and agents to control release such as polyacrylic copolymer(e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agentsand stabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which may contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for a mammal of from about 0.05 to 100 mg/kg of bodyweight of active compound per day, which may be administered in a singledose or in the form of individual divided doses, such as from 1 to 4times per day. It-will be understood that the specific dose level andfrequency of dosage for any:particular subject may be varied and willdepend upon a variety of factors, including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the species, age, body weight, general health, sex and diet ofthe subject, the mode and time of administration, rate of excretion,drug combination, and severity of the particular condition. Preferredsubjects for treatment include animals, most preferably mammalianspecies such as humans, and domestic animals such as dogs, cats, horses,and the like. Thus, when the term “patient” is used herein, this term isintended to include all subjects, most preferably mammalian species,that are affected by mediation of p38 enzyme levels.

Compounds of formula (I), including the compounds described in theexamples hereof, have been tested in one or more of the assays describedbelow and have shown activity as inhibitors of p38α/β enzymes and TNF-α.

Biological Assays

Generation of p38 Kinases

cDNAs of human p38α, β and γ isozymes were cloned by PCR. These cDNAswere subcloned in the pGEX expression vector (Pharmacia). GST-p38 fusionprotein was expressed in E. Coli and purified from bacterial pellets byaffinity chromatography using glutathione agarose. p38 fusion proteinwas activated by incubating with constitutively active MKK6. Active p38was separated from MKK6 by affinity chromatography. Constitutivelyactive MKK6 was generated according to Raingeaud et al. [Mol. Cell.Biol., 1247-1255 (1996)].

TNF-α Production by LPS-Stimulated PBMCs

Heparinized human whole blood was obtained from healthy volunteers.Peripheral blood mononuclear cells (PBMCs) were purified from humanwhole blood by Ficoll-Hypaque density gradient centrifugation andresuspended at a concentration of 5×10⁶/ml in assay medium (RPMI mediumcontaining 10% fetal bovine serum). 50 ul of cell suspension wasincubated with 50 ul of test compound (4× concentration in assay mediumcontaining 0.2% DMSO) in 96-well tissue culture plates for 5 minutes atRT. 100 ul of LPS (200 ng/ml stock) was then added to the-cellsuspension and the plate was incubated for 6 hours at 37° C. Followingincubation, the culture medium was collected and stored at −20° C. TNF-αconcentration in the medium was quantified using a standard ELISA kit(Pharmingen-San Diego, Calif.). Concentrations of TNF-α and IC₅₀ valuesfor test compounds (concentration of compound that inhibitedLPS-stimulated TNF-α production by 50%) were calculated by linearregression analysis.

p38 Assay

The assays were performed in V-bottomed 96-well plates. The final assayvolume was 60 μl prepared from three 20 μl additions of enzyme,substrates (MBP and ATP) and test compounds in assay buffer (50 mM TrispH 7.5, 10 mM MgCl₂, 50 mM NaCl and 1 mM DTT). Bacterially expressed,activated p38 was pre-incubated with test compounds for 10 min. prior toinitiation of reaction with substrates. The reaction was incubated at25° C. for 45 min. and terminated by adding 5 μl of 0.5 M EDTA to eachsample. The reaction mixture was aspirated onto a pre-wet filtermatusing a Skatron Micro96 Cell Harvester (Skatron, Inc.), then washed withPBS. The filtermat was then dried in a microwave oven for 1 min.,treated with MeltilLex A scintillation wax (Wallac), and counted on aMicrobeta scintillation counter Model 1450 (Wallac). Inhibition datawere analyzed by nonlinear least-squares regression using Prizm(GraphPadSoftware). The final concentration of reagents in the assaysare ATP, 1 μM; [γ-³³P]ATP, 3 nM,; MBP (Sigma, #M1891), 2 μg/well; p38,10 nM; and DMSO, 0.3%.

TNF-α Production by LPS-Stimulated Mice

Mice (Balb/c female, 6-8 weeks of age, Harlan Labs; n=8/treatment group)were injected intraperitoneally with 50 ug/kg lipopolysaccharide (LPS; Ecoli strain 0111:B4, Sigma) suspended in sterile saline. Ninety minuteslater, mice were sedated by CO₂:O₂ inhalation and a blood sample wasobtained. Serum was separated and analyzed for TNF-alpha concentrationsby commercial ELISA assay per the manufacturer's instructions (R&DSystems, Minneapolis, Minn.).

Test compounds were administered orally at various times before LPSinjection. The compounds were dosed either as suspensions or assolutions in various vehicles or solubilizing agents.

ABBREVIATIONS

For ease of reference, the following abbreviations are employed herein,including the methods of preparation and Examples that follow:

-   Ph=phenyl-   Bz=benzyl-   t-Bu=tertiary butyl-   Me=methyl-   Et=ethyl-   Pr=propyl-   Iso-P=isopropyl-   MeOH=methanol-   EtOH=ethanol-   EtOAc=ethyl acetate-   Boc=tert-butyloxycarbonyl-   DCM=dichloromethane-   DCE=1,2-dichloroethane-   DMF=dimethyl formamide-   DMSO=dimethyl sulfoxide-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   HATU=O-(7-Azabenzotriazol- 1-yl-N,NNN′,N′-tetramethyluronim    hexafluorophosphate-   KOH=potassium hydroxide-   K₂CO₃=potassium carbonate-   POCl₃=phosphorous oxychloride-   EDC or EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide    hydrochloride-   DIPEA=diisopropylethylamine-   HOBt=1-hydroxybenzotriazole hydrate-   m-CPBA=m-chloroperbenzoic acid-   NaH=sodium hydride-   NaOH=sodium hydroxide-   Pd=palladium-   Pd/C=palladium on carbon-   min=minute(s)-   L=liter-   mL=milliliter-   μL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=moles-   mmol=millimole(s)-   meq=milliequivalent-   RT or rt=room temperature-   ret. t.=HPLC retention time (minutes)-   sat or sat'd=saturated-   aq.=aqueous-   TLC=thin layer chromatography-   HPLC=high performance liquid chromatography-   RP HPLC=reverse phase HPLC-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS=mass spectrometry-   NMR=nuclear magnetic resonance-   mp=melting point

In the Examples, designations associated with HPLC data reflect thefollowing conditions:

-   a. Column: YMC ODSA S-5 5u C18 4.6×50 mm; Solvent: solvent A=10%    MeOH/90% water/0.1% THF,-and solvent B=90% MeOH/10%water/0.1% THF;    Method: 4 min gradient;-   b. Column: YMC s5 ODS 4.6×50 mm; Solvent: solvent A=10% MeOH/90%    water/0.2% H₃PO₄, and solvent B=90% MeOH/10% water/0.2% H₃PO₄;    Method: 4 min gradient.

Methods of Preparation

Compounds of formula I may generally be prepared according to thefollowing schemes and the knowledge of one skilled in the art, and/orthe methods described in U.S. Pat. Nos. 6,670,357 and/or 6,982,265,incorporated herein by reference. In the schemes, the groups R₁-R₇, X,Y, m, n and p are as described herein for compounds of Formula (I). Thereference to “B” is intended to encompass an optionally-substitutedcycloalkyl, heterocyclo, or heteroaryl ring in formula (I), includingwithout limitation the rings shown as:

Commercially-available compound (1) can be reacted with oxalyl chloridewith heating and then concentrated in vacuo and reacted with an amineB—NH₂ in the presence of a base, such as diisopropylamine, in an organicsolvent, such as DCM to yield compound (2). Compound (2) can be reactedwith hydrogen in the presence of a catalyst, such as Pd, in an alcoholicsolvent, such as EtOH, at rt to afford compound (3). Compound (3) canthen be used as in Scheme 2 to produce compounds (8) of Scheme 2.

3-methyl-1-pyrrole-2,4-diethyl ester can be reacted with chloramine inether to produce compound (4). Reacting compound (4) in formamide withacetic acid produces compound (5). Compound (5) can be reacted withDIPEA and POCl₃ in toluene to produce compound (6). Compound (6) can bereacted with DIPEA and compound (3) in DMF to produce compound (7).Compound (7) can be reacted in THF with NaOH to produce an acidintermediate which upon treatment with HOBt, EDCI and the appropriateamine (NR₂R₁₀) in DMF produces compounds (8).

Compound (3) can be prepared by 1) reacting commercially-available4-amino-3-methylbenzoic acid and N-(tert-butoxycarbonyl)anhydride in THFto produce a Boc-protected aniline intermediate; 2) reacting the anilineintermediate with -(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride, HOBt, and DMF, followed by addition of methoxyaminehydrochloride and DIPEA to produce a BOC-protected N-methoxyamideintermediate; and 3) reacting that methoxyamide intermediate in asolution of HCl in dioxane to produce compound (3) as a hydrochloridesalt. Alternatively, compound (3) can be prepared as shown in Scheme 1.

A substituted hydroxamate (9) can be reacted with acid, such as HCl, inanhydrous MeOH, to afford compound (10). Compound (10) can be reactedwith an aq. base such KOH with heating to form compound (11). Compound(11) is reacted with an amine B—NH₂ in the presence of a couplingreagent, such as HATU, and a base such as diisopropylamine, in anorganic solvent, such as N-methylpyrrolidinone to afford compounds (12).Hydroxamate (9) can be prepared as outlined in Schemes 1 and 2 and/or asshown in U.S. patent application Ser. No. 10/036,293.

Commercially-available compound (13) can be reacted with a sulfonylchloride in the presence of a base, such as TEA, in an organic solvent,such as DCM to yield compound (14). Reaction of compound (14) withhydrogen in the presence of a catalyst, such as Pd in a solvent, such asMeOH, yields compound (15). Reaction of compound (15) with chloride (6)(see scheme 2) in an organic solvent, such as DMF, at rt affordscompound (16).

Reaction of compound (16) with aq. KOH with heating affords compound(17). Compound (17) can be reacted with an amine R₂NH₂ in the presenceof a coupling reagent, such as EDCI, and a base such asdiisopropylamine, in an organic solvent, such as DMF to afford compound(18).

Chloropyrrolotriazine (6) (see Scheme 2) can be reacted with an aniline(13) (e.g, see Scheme 4) in anhydrous DMF at rt to afford compound (19).Reaction of compound (19) with an aq. base such as NaOH with heatingaffords compound (20). Compound (20) can be reacted with an amine R₄NH₂in the presence of a coupling reagent, such as HOBt, with or without abase such as diisopropylamine, in an organic solvent, such as DMF toafford compound (21). Compound (21) can be reacted with hydrogen in thepresence of a catalyst, such as Pd/C, in an organic solvent, such asMeOH to afford compound (22). Reaction of compound (22) with anisocyanate in an organic solvent, such as DCE affords compound (23).

Commercially-available compound (13), can be reacted with carbonyldiimidazole and an amine B—NH₂ in an organic solvent, such as DCE, toyield compound (24). Reaction of compound (24) with hydrogen in thepresence of a catalyst, such as Pd, in an alcoholic solvent such as EtOHaffords compound (25). Reaction of (25) with chloride (6) in an organicsolvent, such as DMF, affords compound (26). Reaction of (26) with aq.NaOH with heating affords product (27). Product (27) can be reacted withan amine R₄NH₂ in the presence of a coupling reagent, such as EDCI, anda base such as diisopropylamine, in an organic solvent, such as DMF toafford compound (28).

Scheme 7 shows methods for making compounds (4a) (see scheme 2), whereinR₃ is amino (4b), halogen (4c), or cyano (4d). Glycine ethyl ester (29)can be added to an alkyl alkoxy methylene cyanoacetate at from rt to 80°C. to obtain compound (30). Compound (30) is cyclized to form pyrrole(4b) upon treatment with a strong base, such as lithiumhexamethyldisilazane, at from −78° C. to rt in an organic solvent suchas THF. Pyrrole (4b) can be converted to a halide using sodium nitritein an organic solvent, such as DMF, and a halide source, such as CuBr toyield compound (4c). Compound (4c) can be converted to compound (4d)using CuCN in an organic solvent such as NMP at elevated temperatures.Alternatively, compound (4b) can be directly converted to compound (4d)using sodium nitrite in an organic solvent, such as DMF, and a cyanidesource such as CuCN. Compounds (4a)-(4d) can be used as described inprevious schemes (e.g., Scheme 2), to form compounds of Formula (I)herein.

Reduction of the ester group of pyrrolotriazine 5 (see Scheme 2) with asuitable reducing agent such as LAH in an aprotic organic solvent suchas THF produces the alcohol (31). Alcohol (31) is oxidized to thealdehyde (32) with a suitable oxidant, such as Jones Reagent. Aldehyde(32) is reacted with a suitable organometallic reagent (such asphenylmagnesium bromide) to afford an intermediate secondary alcoholproduct that is subsequently oxidized to ketone (33) with a suitableoxidant, such as Jones Reagent. A chlorinating agent, such as POCl₃, isused to convert (33) to chloride (34). Chloride (34) is reacted with ananiline in a suitable solvent, such as DMF, at rt or elevatedtemperature to provide product (35), a compound of formula (I).

Coupling of compound (6) (see Scheme 2), with the appropriate aminobenzoic acid in DMF affords compound (36). Reduction of the ester groupof compound (36), with a suitable reducing agent such as DIBAL-H in anaprotic organic solvent such as THF produces the alcohol (37). Alcohol(37) can be reacted with an amine RNH₂ in the presence of a couplingreagent, such as BOP, in an organic solvent, such as DMF, to afford theproduct (38). Product (38) is oxidized to aldehyde (39) with a suitableoxidant, such as MnO₂, in an organic solvent such as THF. Aldehyde (39)is reacted with a suitable organometallic reagent (such asphenylmagnesium bromide) to afford an intermediate secondary alcoholproduct that is subsequently oxidized to the ketone (40) with a suitableoxidant, such as PCC.

In addition, other compounds of formula I may be prepared usingprocedures generally known to those skilled in the art. In particular,the following examples provide additional methods for the preparation ofthe compounds of this invention.

The invention will now be further described by the following workingexamples, which are preferred embodiments of the invention. HPLCpurifications were done on C18 reverse phase (RP) columns using waterMeOH mixtures and TFA as buffer solution. These examples areillustrative rather than limiting. There may be other embodiments thatfall within the spirit and scope of the invention as defined by theappended claims.

EXAMPLE 1

Step A:

To a solution of 3-amino-4-methylbenzoic acid (5.12 g, 33.9 mmol, 1.0eq.), EDC (9.97 g, 52.0 mol, 1.5 eq.) and 4-(dimethylamino)pyridine(0.89 g, 7.3 mol, 0.2 eq.) in DMF (100 mL) at 0° C. was addedcyclopropylamine (4.0 mL, 57.7 mol, 1.7 eq.) dropwise. After stirringfor 15 min., the cold bath was removed, and the reaction mixture wasstirred at rt overnight. Volatiles were removed at 50° C. under reducedpressure. The residue was diluted with water and extracted with DCM(3×). The organic layers were combined, dried over sodium sulfate, andconcentrated in vacuo to give an oil. Silica gel chromatography usingDCM:MeOH (20:1) afforded compound 1A as a yellow oil (6.98 g, 108%yield). HPLC Ret. t.=0.637 min.; LC/MS (M+H)⁺=191.09⁺.

Step B:

To a suspension of the starting oxopyrrolotriazine (3.00 g, 13.6 mmol)in toluene (45 mL) was added dropwise phosphorus oxychloride (1.90 mL,20.4 mmol) and N,N-DIPEA (2.37 mL, 13.6 mmol) successively at rt. Theresulting mixture was heated at reflux for 36 h, allowed to cool to rt,and then poured into an ice-cold mixture of sat'd sodium bicarbonatesolution (150 mL) and toluene (60 mL). The organic layer was separatedand the aqueous layer extracted with toluene (3×50 mL). The combinedextract was washed with sat'd sodium bicarbonate solution and brine anddried over anhydrous MgSO₄. Evaporation of solvent in vacuo affordedcompound 1B (3.26 g, 100% yield) as a yellow solid.

Step C:

EXAMPLE 1

A solution of products 1A (1.60 g, 8.40 mmol, 1.6 eq.) and 1B (1.30 g,5.40 mmol, 1.0 eq.) in DMF (13 mL) was stirred at rt overnight. Waterwas added and the precipitate collected by filtration, washed withwater, and dried. Trituration with diethyl ether afforded Example 1(1.70 g, 80% yield) as an off-white solid. HPLC Ret. t.=3.190 min.;LC/MS (M+H)⁺=394.31⁺.

EXAMPLE 2

A solution of Example 1 (0.86 g, 2.20 mmol, 1.0 eq.) in THF (4.0 mL) and1 N aqueous NaOH (9.0 mL, 4.1 eq.) was stirred at 60° C. overnight.After cooling to rt, the reaction mixture was concentrated in vacuo butnot to dryness. To the solution at 0° C. was added 1 N aqueoushydrochloric acid until it was acidic and the precipitate was collectedand dried to afford crude Example 2 (0.51 g, 64.0% yield). HPLC Ret.t.=2.400 min.; LC/MS (M+H)⁺=366.06⁺. The filtrate was then extractedwith EtOAc (3×) and the organic layers were combined, dried over sodiumsulfate, and concentrated in vacuo to give Example 2 (0.035 g, 4.4%yield).

EXAMPLE 3

A solution of Example 2 (0.026 g, 0.071 mmol, 1.0 eq.), EDC (0.021 g,0.11 mmol, 1.5 eq.), HOBt (0.015 g, 0.11 Immol, 1.5 eq), n-butylamine(0.015 mL, 0.15 inmol, 2.1 eq.) and DIPEA (0.040 mL, 0.23 mmol, 3.2 eq.)in DMF (0.20 mL) was shaken at rt overnight. Water (1 mL) was added andthe precipitate collected by filtration, washed with water, and dried togive Example 3 (0.021 g, 70% yield); HPLC Ret. t.=2.883 min.; LC/MS(M+H)⁺=421.18⁺.

EXAMPLES 4 TO 22

Compounds having the formula (Id), above, wherein R₄ has the valueslisted in the following Table, were prepared following the sameprocedure described for Example 3, using the appropriate amine in placeof n-butylamine.

Ex. # R₄ (M + H)⁺ HPLC Ret. t. (min) 4

393.30 2.29^(a) 5

407.27 2.51^(a) 6

469.35 3.08^(a) 7

407.21 2.56^(a) 8

421.18 2.88^(a) 9

423.17 2.22^(a) 10

495.26 2.22^(a) 11

513.15 3.16^(a) 12

405.07 2.34^(a) 14 CH₃— 379.17 2.05^(a) 15

478.17 1.61^(a) 16

423.20 2.03^(a) 17

421.22 2.74^(a) 18

485.92 2.68^(a) 19

499.59 2.89^(a) 20

456.19 1.74^(a) 21

456.18 1.67^(a) 22

456.16 1.67^(a)

EXAMPLES 23 AND 24

Compounds having the formula (Ie), above, wherein R₄ has the valueslisted in the following Table, were prepared following the sameprocedure described for Example 3, using piperizinylamine andmorpholinylamine in place of n-butylamine.

Ex. # R₄ (M + H)⁺ HPLC Ret. t. (min) 23

433.12 2.73^(a) 24

435.44 2.08^(a)

EXAMPLES 25 TO 27

Compounds having the formula (If), wherein R₄ has the values listed inthe Table provided below, were prepared following the same proceduredescribed for Examples 1 through 3, using the appropriate amine in placeof n-butylamine, and in place of cyclopropylamine in Step 1A,(±)-trans-ethoxycyclopropylamine, which was prepared following StepsA-D, below.

Step A:

To a well stirred mixture of ethyl vinyl ether (47.9 mL, 0.500 moL) andRhodium (II) acetate dimer (0.221 g, 0.500 mmol) in diethyl ether (10mL) was slowly introduced ethyl diazoacetate (10.5 mL, 0.100 mol) indiethyl ether (30 mL) via a syringe pump at rt over 8 hours. Theinsoluble material was removed by filtration through Celite, and theexcess ethyl vinyl ether and solvent were evaporated in vacuo. Theresidue was distilled in vacuo to give product 25A (10.3 g, 65% yield)as a colorless oil which was a mixture of cis and trans isomers in aratio of approximately 1:1.

Step B:

To a solution of product 25A (10.3 g, 65.4 mmol) in MeOH (200 mL) wasadded a solution of NaOH (7.85 g, 196.2 mmol) in one portion, and theresulting solution was heated at reflux for 5 h. The mixture wasconcentrated under vacuum. The residue was acidified with 6 N HCl topH=2 and extracted with EtOAc (5×). The combined organic phase was driedover MgSO₄. Evaporation of solvent in vacuo gave product 25B (8.46 g,99% yield) as a colorless oil which was a mixture of cis and transisomers in a ratio of approximately 1:1.

Step C:

A mixture of product 25B (1.00 g, 7.68 mmol), diphenylphosphoryl azide(1.82 mL, 8.44 mmol), and TEA (1.18 mL, 8.47 mmol) in anhydrous t-BuOH(30 mL) was heated at 90° C. for 27 h. The volatiles were evaporated invacuo. The residue was diluted with 10% Na₂CO₃ solution (30 mL) andextracted with diethyl ether (4×30 mL). The combined organic phase waswashed with brine, dried over MgSO₄, and the solution was concentratedin vacuo. Silica gel chromatography (40% Et₂O/hexane) of the residueafforded product 25C (0.901 g, 58% yield) as a colorless oil which was amixture of cis and trans isomers in a ratio of approximately 15:85 infavor of trans isomer.

Step D:

A mixture of product 25C (0.881 g, 4.38 mmol) and 1 N HCl (20 mL) washeated at reflux for 5 h. After it was allowed to cool to rt, themixture was extracted with diethyl ether. The aqueous layer was adjustedto pH=11 with 1 N NaOH solution, and then extracted with diethyl ether(4×). The combined organic phase was dried over MgSO₄ and evaporation ofthe solvent gave (±)-trans-ethoxycyclopropylamine (0.224 g, 50% yield)as a slightly yellow oil.

Ex. # R₄ (M + H)⁺ HPLC Ret. t. (min) 25

437.23 2.29^(a) 26

451.24 2.44^(a) 27

513.23 2.92^(a)

EXAMPLE 28

To a solution of Example 27 (30.0 mg, 0.0585 mmol) in DCE (6 mL) wasadded BBr₃ at 0° C. The resulting mixture was stirred at rt for 20 min.,then quenched with water. The mixture was adjusted to pH=9 with sat'dNa₂CO₃ solution and extracted with EtOAc (3×). The combined organicphase was washed with brine and dried over MgSO₄. The solution wasconcentrated under vacuum and silica gel chromatography (6% MeOH/CHCl₃)of the residue afforded Example 28 (3.2 mg) as a white solid. HPLC Ret.t.=3.09 min. (b); LC/MS (M+H)⁺=485.38⁺.

EXAMPLES 29 AND 30

Compounds having the formula (Ig), wherein B has the values listed inthe Table provided below, were prepared following the same proceduresdescribed for Examples 1 and 3, using an appropriately-substitutedcyclopropyl amine in Step 1A and ethylamine in place of n-butylamine.

Ex. # B (M + H)⁺ HPLC Ret. t. (min) 29

469.50 3.02^(a) 30

411.22 2.26^(a)

EXAMPLE 31

Step A:

Compound 31A was prepared following the procedures described in U.S.patent application Ser. No. 10/036,293, assigned to the presentassignee, which is incorporated herein by reference.

Step B:

A mixture of compound 31A, 3-aminoisoxazole (0.30 mL, 4.06 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(0.720 g, 1.63 mmol), and N-methylmorpholine (0.54 mL, 4.91 mmol) in DMF(4 mL) was heated at 65° C. for two days. The mixture was diluted withEtOAc and washed with water (2×), 10% Na₂CO₃ solution, and brine. Thesolution was concentrated in vacuo and the product isolated bypreparative HPLC. HPLC Ret. t.=2.48 min. (a); LC/MS (M+H)⁺=434.11⁺.

EXAMPLES 32 TO 38

Compounds having the formula (Ig), above, wherein B has the valueslisted in the Table provied below, were prepared following the sameprocedures described for Example 31, using ethylamine in place ofpropylamine to make the starting compound and in Step B, an appropriateaminoheteroaryl in place of aminoisooxazole.

Ex. # B (M + H)⁺ HPLC Ret. t. (min) 32

436.36 2.65^(a) 33

492.62 3.66^(a) 34

450.19 3.01^(a) 35

420.14 2.52^(b) 36

437.13 2.65^(b) 37

420.25 2.23^(b) 38

419.22 2.32^(b)

EXAMPLE 39

Step A:

To a solution of LAH (13.7 g, 362 mmol) in THF (800 mL) was added esterhaving the formula

(8 g, 36.2 mmol) in several portions at rt. The reaction mixture washeated to reflux for 30 min., then cooled to rt, carefully quenched bybeing poured into ice water (1 L), and stirred rapidly for 1 h. Themixture was extracted with EtOAc and the combined extracts were washedwith brine, dried over MgSO₄, filtered, and concentrated to givecompound 39A (5.60 g, 86%).Step B:

To a suspension of compound 39A (1.0 g, 5.58 mmol) in acetone (80 mL) at0° C. was added Jones Reagent (1.9 mL) dropwise. The reaction wasstirred at 0° C. for 1 h, then carefully quenched with 2-propanol. Sat'daq. sodium bicarbonate (100 mL) was added, and the mixture was extractedwith EtOAc (5×100 mL). The combined extracts were washed with sat'd aq.sodium bicarbonate (1×100 mL), water (1×100 mL), and brine (1×100 mL),then dried over MgSO₄, filtered, and concentrated to afford compound 39B(647 mg, 65%). HPLC ret. t. (min): 1.50, MW: 177.16, LCMS[M+H]⁺=178.

Step C:

To a solution of compound 39B (600 mg, 3.39 mmol) in THF (80 mL) at 0°C. was added phenylmagnesium bromide (3M, 2.94 mL, 8.8 mL) dropwise over5 min. After stirring for 30 min at 0° C., the reaction was warmed to rtover 1 h and quenched with sat'd aq. ammonium chloride. The mixture wasextracted with EtOAc and the extracts were dried, filtered, andconcentrated to afford the benzylic alcohol intermediate. The crudebenzylic alcohol was dissolved in acetone (50 mL) and cooled to 0° C.Jones Reagent (1 mL) was added dropwise and the reaction was stirred at0° C. for 1 h, then carefully quenched with 2-propanol. Sat'd aq. sodiumbicarbonate (50 mL) was added and the mixture was extracted with EtOAc(4×50 mL). The combined extracts were washed with sat'd aq. sodiumbicarbonate (1×50 mL), water (1×50 mL), and brine (1×50 mL) before beingdried over MgSO₄, filtered, and concentrated to afford compound 39C (563mg, 66% over 2 steps). HPLC ret .t. (min): 2.82, MW: 253.26,LCMS[M+H]⁺=254.

Step D:

Ketone 39C (152 mg, 0.6 mmol) was placed in POCl₃ (5 mL) and heated to100° C. for 1.75 h. The reaction was cooled to rt and the excess POCl₃was evaporated under vacuum. The residue was dissolved in anhydrous DCM(10 mL) and added dropwise to a rapidly stirred solution of sat'd aq.sodium bicarbonate (50 ml) and DCM (50 mL) at 0° C. The mixture wasstirred for 1 h, then the aqueous phase was extracted with DCM (3×50mL). The organic phases were washed with sat'd aq. sodium bicarbonate(1×50 mL), water (1×50 mL), and brine (1×50 mL), then dried over MgSO₄,filtered, and concentrated to afford the chloride 39D (163 mg, 100%).

Step E:

To a solution of the chloride 39D (31.5 mg, 0.116 mmol) in DMF (1 mL)was added 3-amino-N-cyclopropyl-4-methyl-benzamide (compound 1A) (44 mg,0.23 mmol) and the solution was heated to 60° C. for 3 h. Water (5 mL)was added to precipitate the product, which was collected by filtration,washed with water, and allowed to air dry to give Example 39. HPLC ret.t. (min): 3.34, MW: 425.49, LCMS[M+H]⁺=426.

EXAMPLES 40 TO 42

Compounds having the formula (Ih), wherein Y and B have the valueslisted in the Table provided below, were prepared following the same orsimilar procedure as described above for Example 39, using theappropriate amine in step E.

HPLC ret. MS Ex. time (M + No. Y B MW (min.) H)+ 40 —C(═O)NH—

564.62 3.87 565 41 —C(═O)NH— —CO₂CH₃ 443.47 3.25 444 42 —NHC(═O)—

564.62 3.50 565

EXAMPLE 43

Step A:

To a solution of compound 39D (60 mg, 0.221 mmol) in DMF (1 mL) wasadded 3-amino-4-methyl-benzoic acid (66.8 mg, 0.442 mmol) and thesolution was heated to 60° C. for 3 h. Water (5 mL) was added toprecipitate the product, which was collected by filtration, washed withwater, and allowed to air dry to give compound 43A (75 mg, 88%). HPLCret. t. (min): 3.38, MW: 386.41, LCMS[M+H]⁺=387.

Step B:

To a solution of the acid 43A (30 mg, 0.078 mmol) and HATU (44 mg, 0.117mmol) and DIPEA(17 μL, 0.1 mmol) in DMF (0.5 mL) at rt was added3-amino-isoxazole. The reaction was stirred at rt for 1 h, and water (5mL) was added to precipitate the product, which was collected byfiltration, and purified by preparative HPLC to afford Example 43. HPLCret. t. (min): 3.39, MW: 452.48, LCMS[M+H]⁺=453.

EXAMPLE 44

Step A:

To a solution of the compound 39B (160 mg, 0.90 mmol) in THF (10 mL) at0° C. was added 6-methyl-2-pyridylmagnesium bromide (0.25M, 14.4 mL, 3.6mM) dropwise over 5 min. After stirring for 30 min at 0° C., thereaction was warmed to rt and stirred for 16 h. Additional aliquots of6-methyl-2-pyridylmagnesium bromide were added to complete theconversion of the starting material and the reaction was quenched withsat'd aq. ammonium chloride. The mixture was extracted with EtOAc andthe extracts were dried, filtered, and concentrated to afford a reddishbrown semi-solid material. This material was dissolved in acetone (10mL) and cooled to 0° C. Jones Reagent (0.4 mL) was added dropwise andthe reaction was stirred at 0° C. for 1 h, then carefully quenched with2-propanol. Sat'd aq. sodium bicarbonate (15 mL) was added and themixture was extracted with EtOAc (4×20 mL). The combined extracts werewashed with sat'd aq. sodium bicarbonate (1×20 mL), water (1×20 mL), andbrine (1×20 mL), then dried over MgSO₄, filtered, and concentrated toafford compound 44A (145 mg, 60% over 2 steps).

Step B:

Ketone 44A (75 mg, 0.28 mmol) was placed in POCl₃ (4 mL) and heated to100° C. overnight. The reaction was cooled to rt and the excess POCl₃was evaporated under vacuum. The residue was dissolved in anhydrous DCM(10 mL) and added dropwise to a rapidly stirred solution of sat'd aq.sodium bicarbonate (50 ml) and DCM (50 mL) at 0° C. The mixture wasstirred for 1 h, then the aqueous phase was extracted with DCM (3×50mL). The organic phases were washed with sat'd aq. sodium bicarbonate(1×50 mL), water (1×50 mL), and brine (1×50 mL), then dried over MgSO₄,filtered, and concentrated to afford the chloride 44B (64 mg, 79%).

Step C:

EXAMPLE 44

To a solution of compound 44B (53 mg, 0.18 mmol) in DMF (0.5 mL) wasadded compound 1A (84 mg, 0.44 mmol) and the solution was heated to 60°C. for 2 h. Water (5 mL) was added to precipitate the product, which wascollected by filtration, washed with water, and allowed to air dry toafford Example 44 (34.2 mg, 41%). HPLC ret. t. (min):3.39, MW: 452.48,LCMS[M+H]⁺=453.

EXAMPLE 45

Example 45 was prepared following the same procedure as in Example 44,using a different benzamide in Step C. HPLC ret. t. (min):3.22, MW:467.49, LCMS[M+H]⁺=468.

EXAMPLE 46

Step A:

To a solution of the chloride having the formula

(10 g, 41.8 mmol) in DMF (60 mL) was added 3-amino-4-methyl-benzoic acid(6.3 g, 41.8 mmol) at rt. The reaction mixture was stirred for 16 h,poured into water (500 mL) and stirred rapidly for 1 h. The solids werefiltered, washed with water (500 mL), and air dried to give the compound46A (13.6 g, 92%) as a light pink solid. MS[M+H]⁺=355.Step B:

To a solution of the compound 46A (1 g, 2.8 mmol) in DCM (6 mL) at −78°C. was added DIBAL-H (1M, 8.5 mL, 8.5 mmol) dropwise. The reaction wasstirred for 2 h at −78° C., warmed to rt over 1.5 h, quenched with sat'daq. NH₄Cl, then HCl (1 N) was added to adjust the pH to 4 and thesolution was extracted with EtOAc. After drying of the organic phasesand concentration, compound 46B was obtained as a pink solid (874 mg,100%). HPLC ret. t. (min): 1.74, MW: 312.33, and LCMS[M+H]⁺=313.

Step C:

EXAMPLE 46

To a solution of compound 46B (1.8 g, 5.9 mmol) in DMF (10 mL) was addedBOP (2.9 g, 615 mmol), cyclopropylamine (2 mL, 29.8 mmol). The reactionwas stirred overnight at rt, then poured into water (60 mL) toprecipitate the product. The solids were collected by filtration andpurified by preparative HPLC to give Example 46 (1.5 g, 74%). HPLC ret.t. (min): 1.64, MW: 351.41, LCMS[M+H]⁺=352.

EXAMPLE 47

To a solution of Example 46 (1.5 g, 4.3 mmol) in THF (30 mL) at rt wasadded MnO₂ (5.4 g, 64 mmol). After stirring for 40 min., the reactionwas completed. The product was collected by filtration and theprecipitate was washed with acetonitrile. After drying of the filtrateand concentration, Example 47 was obtained as a yellow oil (1.5 g,quantitative). HPLC ret. t. (min): 2.52, MW: 349.40, LCMS[M+H]⁺=350.

EXAMPLE 48

To a solution of 2-bromopyridine (54 μl, 0.57 mmol) and TMEDA (85 μl,0.57 mmol) in THF (10 mL) at −78° C. was added nBuLi (1.6 M, 356 μl,0.57 mmol) dropwise. To this solution was added Example 47 (50 mg, 014mmol). The reaction was stirred for 0.5 h at −78° C., then warmed to rtand quenched with water. The mixture was extracted with EtOAc and theextracts were dried, filtered, and concentrated to afford the crudeintermediate alcohol. To a solution of the crude alcohol in DCM (5 mL)at rt was added pyridinium chlorochromate (24.1 mg, 0.11 mmol). Afterstirring 1 h, the reaction was quenched with water (2 mL). The desiredproduct was extracted with EtOAc and dried. After purification bypreparative HPLC, Example 48 was obtained as yellow solid (24.6 mg,40%). HPLC ret. t. (min): 2.95, MW: 426.48, LCMS[M+H]⁺=427.

EXAMPLES 49 TO 68

Compounds having the structure

were prepared according to the procedure described for example 3 usingthe appropriate amine in place of n-butylamine.

Ex. # R₄ (M + H)⁺ HPLC Ret. t. (min) 49

419.3 2.60 50

457.3 2.13 51

457.2 2.22 52

418.2 2.56 53 H 365.3 1.78 54

470.3 1.76 55

524.1 2.79 56

421.2 2.79 57

449.2 2.45 58

449.3 2.45 59

437.2 2.40 60

476.3 1.82 61

473.3 1.68 62

476.2 1.73 63

462.3 1.68 64

451.3 2.63 65

450.2 1.6 66

505.2 1.92 67

492.4 1.62 68

423.2 2.08

EXAMPLE 69

Step 1, Intermediate A:

To a rt solution of 3-fluoropyridine (5.0 g) in dichloromethane (25 mL)and 30% aqueous hydrogen peroxide (10 mL) was added methyltrioxorhenium(25 mg) and the resulting mixture was stirred overnight. Manganese oxide(25 mg) was added and the solution was stirred at rt for an additionalhour. Sodium chloride was added to saturate the aqueous portion and thelayers were separated. The aqueous portion was extracted with additionaldichloromethane (3×100 mL) and the combined organic extracts were driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo toprovided a light yellow oil which solidified upon standing to affordproduct A as a light yellow solid (4.92 g, 84%). HPLC Ret. Time: 0.30min.

Step 2, Intermediate B:

To solution of intermediate A (2.85 g, 25.2 mmol) in dichloromethane (25ml) at rt was added trimethylsilylcyanide (10.0 ML, 75.6 mmol) and themixture was refluxed for 10 h. After cooling to rt, saturated aqueoussodium bicarbonate solution (30 mL) was added and the resulting mixturewas extracted with dichloromethane (3×150 mL). The combined organicextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to provided a light brown oil (4.60 g) as thecrude product. This material was purified by flash column chromatographyon silicas gel eluting with 30% ethyl acetate in hexane to provide alight tan oil which solidified upon standing to give product B as alight tan solid (2.48 g, 84). HPLC Ret. Time: 1.03 min.

Step 3, Intermediate C:

To intermediate B (1.40 g) in ethanol (50 ml) were successively added10% palladium on carbon (500 mg) and concentrated hydrogen chloride (2.9ml) and the resulting mixture was shaken under hydrogen (40 psi) for 20h. The solution was filtered through a bed of celite and the filtratewas concentrated in vacuo to give 1.80 g of product C as a white solid.HPLC Ret. Time: 0.19 min.

Step 4, Title Compound:

A mixture of intermediate D (40 mg, 0.11 mmol), EDAC (25 mg, 0.13 mmol),and HOBt (16 mg, 0.12 mmol) in 0.3 mL of anhydrous DMF was stirred at rtfor 2 hr then the amine hydrochloride C (0.13 mmol) and Hunig's base (38μL, 0.22 mmol) were successively added. After stirring overnight at rt,the crude reaction mixture was subjected to purification byreverse-phase preparative HPLC to give the title compound.

EXAMPLES 70 AND 71

Examples 70 and 71 were prepared in the same manner as described forExamples 23-24.

Ex. R₄ (M + H)⁺ HPLC Ret. t. (min) 70

437.3 2.19 71

393.2 2.04

EXAMPLE 72

Step 1, Intermediate F:

To intermediate E (10.0 g, 45.2 mmol) in POCl₃ (30 mL) at rt under argonwas slowly added anhydrous DMF (7.0 mL, 90.4 mmol) and the resultingmixture was heated at 95° C. for 15 hours. After cooling to rt, thecontents were slowly poured into a well-stirred mixture of 1 L ofsaturated aq. sodium bicarbonate solution and 200 mL of crushed ice.After allowing the heterogeneous slurry to stir at rt for 2.5 h, theresulting solid was collected by vacuum filtration and the solid waswashed with two 150 mL portions of water then allowed to partially dryin the funnel. The solid was finally washed with two portions ofdichloromethane (100 mL each) and the resulting organic filtrate wasdried over anhydrous sodium sulfate and concentrated in vacuo to provideproduct F as a yellow solid (5.35 g, 47%) which was used directlywithout further purification. HPLC Ret. Time: 2.96 min.

Step 2, Intermediate G:

Intermediate F (3.19 g, 11.9 mmol) and the corresponding anilinehydrochloride (3.52 g, 15.5 mmol) in 40 mL of anhydrous DMF were stirredat rt overnight then diluted with 200 mL of water and 30 mL of saturatedaqueous sodium bicarbonate solution. After stirring at rt for 1 h, theresulting solid was collected by vacuum filtration, washed with water,and dried in vacuo to afford product G as an orange solid (4.2 g, 84%)which was used directly without further purification. HPLC Ret. Time:2.97 min. MH⁺=422.1 (m/z).

Step 3, Title Compound:

To intermediate G (0.8 g, 1.90 mmol) in anhydrous THF (10 mL) at rtunder argon were successively added 1-methylpiperazine (0.24 g, 2.47mmol) and NaBH(OAc)₃ (1.21 g, 5.70 mmol) followed by stirring at rt for3 hour. The reaction mixture was quenched by addition of 50 mL ofmethanol followed by stirring for an additional hour at rt thenconcentrated and partitioned between 50 mL of saturated aqueous sodiumbicarbonate solution and 200 ml of ethyl acetate. The layers wereseparated and the aqueous portion was saturated with sodium chloride andextracted with additional ethyl acetate (4×100 mL ). The combinedorganic extracts were dried over anhydrous sodium sulfate andconcentrated in vacuo to give the title compound as a light yellow solid(1.02 g, yield 89%). HPLC Ret. Time: 2.25 min. MH+ (m/z) 506.2.

EXAMPLES 73 TO 80

The following compounds were prepared in the same manner as describedfor Example 72.

Example Structure Retention Time MH+ 73

2.23 493.2 74

2.26 451.2 75

2.40 479.2 76

2.38 491.2 77

2.32 477.3 78

2.26 507.3 79

3.29 499.3 80

2.13 492.2

EXAMPLES 81 TO 83

Step 1, Intermediate H:

To compound 4 (0.80 g, 1.67 mmol) in methanol (10 mL) at rt was added 6Naqueous sodium hydroxide solution (1.8 mL, 10.8 mmol) and the mixturewas refluxed for 20 h. After cooling to rt, the methanol was removed invacuo and the mixture was brought to pH 6 with 1N HCl and freeze driedto give 1.02 g of the crude product H as a pale yellow solid containingresidual sodium chloride. This material was used without furtherpurification in the subsequent reaction. HPLC Ret. Time: 1.65 min. MH⁺(m/z) 478.14.

Step 2, Title Compounds:

Intermediate H (40 mg, 0.083 mmol), EDAC (25 mg, 0.13 mmol), and HOBt(16 mg, 0.12 mmol) were stirred at rt for 2 hr then the correspondingamine RNH₂ (0.13 mmol) and Hunig's base (38 μL, 0.22 mmol) weresuccesively added followed by stirring overnight at rt. The resultingmixture was subjected to reverse-phase preparative HPLC to obtain thetitle compounds.

Ex. Structure Retention Time MH+ 81

1.43 491.2 82

1.61 505.2 83

1.82 519.2

EXAMPLES 84 TO 86

Examples 84-86 were prepared from intermediate H as follows:

Intermediate H (40 mg, 0.083 mmol), EDAC (25 mg, 0.13 mmol), and HOBt(16 mg, 0.12 mmol) were stirred at rt for 2 hr then the correspondingalcohol ROH (1 mL) and Hunig's base (38 μL, 0.22 mmol) were succesivelyadded followed by stirring overnight at rt. The resulting mixture wassubjected to reverse-phase preparative HPLC to obtain the titlecompounds.

Example Structure Retention Time MH+ 84

2.00 492.3 85

2.54 520.6 86

2.45 520.3

EXAMPLE 87

To a solution of aldehyde [Example 47] (0.040 g, 0.114 mmol) in DMF (1mL) at rt was added 2-chloroquinoxaline (0.0188 g, 0.114 mmol), sodiumhydride (0.0054 mg, 0.138 mmol), N,N′-dimethylimidazolium iodide (0.084mg, 0.038 mmol), and p-toluenesulfinic acid, sodium salt (0.008 mg,0.044 mmol). After stirring overnight at rt, the solution was heated to80° C. and additional portions of N,N′-dimethylimidazolium iodide andsodium hydride were added. After 1 h the reaction was cooled to rt andwater was added. The resulting precipitate was collected and furtherpurified by preparative reverse phase HPLC to afford the title compound(0.003 g).). HPLC ret. t. (min): 3.61, MW: 477.5, LCMS[M+H]⁺=478.

EXAMPLE 88

Step A:

To Example 2 (500 mg) was added thionyl chloride (6 mL) at rt. Afterstirring for 30 min at rt, the thionyl chloride was evaporated underreduced pressure affording 88A as a white solid (HCl Salt, 580 mg)

Step B:

To a solution of acid chloride 88A (0.020 g, 0.048 mmol) and anisole(0.026 mL, 0.238 mmol) in 1,2-dichloroethane (1 mL) at 0° C. was addedaluminum trichloride (0.0095 g, 0.071 mmol). After 2 hr at 0° C. thesolution was warmed to rt and additional aluminum trichloride (0.140 g)was added. After stirring at rt overnight, the reaction was quenchedwith water (0.2 mL) and the solvent was evaporated. The residue wasrecrystallized from a minimum of methanol/water and collected byfiltration to afford the title compound (0.0065 g). ). HPLC ret. t.(min): 3.29, MW: 455.5, LCMS[M+H]⁺=456.

EXAMPLES 89 TO 96

The following compounds were obtained in a manner similar to Example 88.

Ex. Structure MW HPLC ret. t (min) MS (MH+) 89

464.5 3.00 465 90

414.5 2.84 415 91

428.5 3.08 429 92

478.6 3.19 478 93

428.5 2.68 429 94

478.6 2.89 478 95

415.5 2.94 416 96

414.5 2.49 415

EXAMPLE 97

Step A:

A mixture of 3-fluoronitrobenzene (10.0 g, 71 mmol), morpholine (27 mL),and DMSO (118 mL) was stirred at 110° C. for 36 h then cooled to rt andpoured into 800 mL of water. The resulting mixture was stirred for 20min and the solid was collected by vacuum filtration and dried in vacuoto afford 13.6 g (92%) of 97A as a bright yellow solid. ). LCMS(M+H⁺)=209.1. HPLC Ret. time: 1.48 min.

Step B:

To a slurry of 97A (13.6 g, 65 mmol) in methanol (225 mL) at rt weresuccessively added ammonium formate (20.5 g, 326 mmol) and 10% palladiumon charcoal (2.0 g) and the mixture was stirred at rt for 48 h. Theresulting mixture was filtered through a pad of celite and the clearfiltrate was concentrated in vacuo and the resulting residue waspartitioned between water (50 ML) and ethyl acetate (150 mL). The layerswere separated and the aqueous portion was extracted with additionalethyl acetate (2×50 mL). The combined extracts were washed with brine(50 mL), dried over anhydrous sodium sulfate, filtered, and concentratedin vacuo to afford 10.8 g (93%) of 97B as a tan solid. LCMS(M+H⁺)=179.2.

Step C:

To a slurry of 2.0 g (4.2 mmol) of the compound

-   -   (synthesized as described in WO 02/40486)        in 12 mL of anhydrous methanol was added 18 mL of a 4 N solution        of anhydrous hydrochloric acid in dioxane at room temperature.        The resulting clear solution was stirred at room temperature for        16 h and the reaction mixture was concentrated in vacuo. The        resulting oil was dissolved in 16 mL of 1.5 N aqueous potassium        hydroxide solution and heated to 50° C. for 3 h. After cooling        to room temperature, the mixture was diluted with 50 mL of water        and 10% aqueous hydrochloric acid was added until pH was        approximately 3 or 4. The resulting precipitated product was        collected by vacuum filtration and washed with 50 mL of water        and dried in vacuo to afford 1.47 g (99%) of 97C as a white        solid. An analytical sample of 97C was prepared by        recrystallization from 10% aqueous acetonitrile. ¹H NMR (CD₃OD):        δ 8.21 (br s, 1H), 8.11 (br s, 1H), 7.89-7.91 (m, 2H), 7.67 (br        s, 1H), 7.44 (d, 1H, 3.40 (q, 2H), 2.86 (s, 3H), 2.36 (s, 3H),        1.25 (s, 3H). LCMS (M+H⁺)=354.2. HPLC: 2.24 min.        Step D: Title Compound

A mixture of 97C (40 mg, 0.11 mmol), HATU (65 mg, 0.17 mmol),diisopropylamine (20 μL, 0.11 mmol), and 97B (39 mg, 0.22 mmol) in 0.3mL of N-methylpyrrolidinone was heated at 80° C. for 16 h and thereaction mixture was purified by reverse-phase preparative HPLC toafford 41 mg (74%) of the title compound as a light tan solid. ¹H NMR(CD₃OD w/TFA): δ 8.28 (s, 1H), 8.19 (s, 1H), 8.16 (d, 1H), 8.11 (d, 1H),7.84 (s, 1H), 7.71 (d, 1H), 7.58 (t, 2H), 7.47 (d, 1H), 3.44 (q, 2H),2.94 (s, 3H), 2.47 (s, 3H), 1.26 (t, 3H). LCMS (M+H⁺)=497.5. HPLC Ret.time: 3.30 min.

EXAMPLE 98

The title compound was prepared as described for the preparation ofExample 97 by substituting 97C* in Step C with Example compound 70 in WO02/40486. LCMS (M+H⁺)=590.2. HPLC Ret. time: 3.26 min.

EXAMPLE 99

The title compound was prepared as described for the preparation ofExample 97 by substituting 97C* in Step C with Example compound 70 in WO02/40486 and by substituting 97B with 4-aminopyridine in Step D. LCMS(M+H⁺)=506.4. HPLC Ret. time: 2.95 min.

EXAMPLE 100

The title compound was prepared as described for the preparation ofExample 97 by substituting 97C* in Step C with Example compound 70 in WO02/40486 and by substituting 97B with 2-aminopyridine in Step D. LCMS(M+H⁺)=590.2. HPLC Ret. Time: 3.01 min.

EXAMPLES 101 TO 104

The following compounds were prepared in a similar manner as thatdescribed for Example 100.

Ex # Structure (M + H)⁺ HPLC Ret. t. (min) 101

489.5 3.54 102

446.3 2.94 103

503.3 3.64 104

496.1 3.19

EXAMPLE 105

Step A:

A solution of 3-nitro-4-methyl benzoyl chloride (215 mg, 1.08 mmol) andN-tolyl-3-tert-butyl-5-aminopyrazole hydrochloride (287 mg, 1.08 mmol)in dichloromethane (5 mL) was added DIPEA (0.38 mL, 2.2 mmol) and thereaction mixture stirred for 2 h. The reaction was concentrated to anoil which was dissolved in EtOAc (50 mL) and washed consecutively withaq NaHCO₃, water, 1N HCl, water and brine. The organic layer was driedover Na₂SO₄, filtered and concentrated to an oil which was purified viacolumn chromatography (10% then 30% EtOAc/hexane) to give the nitroamide (420 mg, 99%).

The above solids was dissolved in EtOH (156 mL) and added 5% Pd-C (wet,10035 mg) and evacuated and back filled under a hydrogen balloon. Thereaction was stirred for 32 h, filtered and concentrated to a whitesolid which was used without further purification (403 mg, 99%), LRMS363.6 (M+H).

Step B: Title Compound

The title compound was prepared from the intermediate obtained in Step Afollowing the procedure described for Examples 1 and 2.

EXAMPLE 106

Step A:

A mixture of 3,5-difluoronitrobenzene (4.1 g, 26 mmol) and morpholine(11 mL) was heated to 100° C. for 16 h then cooled to rt overnight. Theresulting solid was collected by vacuum filtration and dissolved intomethylene chloride (250 mL) and the solution was successively washedwith 1N aqueous HCl (2×100 mL) and brine (100 mL), then dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo to afford4.0 g (69%) of 106A as a yellow solid. LCMS (M+H⁺)=227.2. HPLC Ret.time: 2.85 min.

Step B:

A mixture of 106A (4.0 g, 18 mmol) and 10% palladium on charcoal (0.4 g)in 150 mL of ethanol was stirred under an atmosphere of hydrogen at rtfor 16 h. The resulting mixture was filtered through a pad of celite andthe filtrate was concentrated in vacuo to afford 3.4 g (96%) of 106B asan off-white solid. LCMS (M+H⁺)=197.1. HPLC Ret. time: 0.92 min.

Step C: Title Compound

The title compound was prepared as described for the preparation ofExample 97 by substituting 97B with 106B in Step D. LCMS (M+H⁺)=532.0.HPLC Ret. time: 3.04 min.

EXAMPLE 107

The title compound was prepared as described for the preparation ofExample 97 by substituting 97C* in Step C with Example compound 70 in WO02/40486 and by substituting 97B with 106B in Step D. LCMS (M+H⁺)=608.5.HPLC Ret. time: 3.52 min.

EXAMPLE 108

Step A:

A mixture of 3-fluoronitrobenzene (1.0 g, 7.1 mmol) and1-methylpiperizine (5 mL) was heated to 130° C. for 3 days. Aftercooling to rt, the mixture was diluted with water (100 mL) and extractedwith ethyl acetate (4×40 mL). Concentration of the combined extractsyielded a dark red oil which was dissolved in dichloromethane (75 mL)and washed with 1 N aqueous HCl (3×25 mL). The combined acidic aqueousextracts were neutralized to pH˜7 by addition of 3 N aqueous potassiumhydroxide solution and extracted with dichloromethane (3×40 mL). Thecombined extracts were washed with brine (40 mL), dried over anhydroussodium sulfate, filtered, and concentrated in vacuo to afford 0.92 g(59%) of 108A as a dark brown oil. LCMS (M+H⁺)=222.1. HPLC Ret. time:0.97 min.

Step B:

108B was prepared as described for the preparation of 106B. LCMS(M+H⁺)=192.3. HPLC Ret. time: 0.17 min.

Step C: Title Compound

The title compound was prepared as described for the preparation ofExample 97 by substituting 97B with 108B in Step D. LCMS (M+H⁺)=527.3.HPLC Ret. time: 2.14 min.

EXAMPLE 109

The title compound was prepared as described for the preparation ofExample 97. LCMS (M+H⁺)=571.4. HPLC Ret. time: 2.22 min.

EXAMPLE 110

Step A:

A mixture of 3-fluoronitrobenzene (1.0 g, 7.1 inmol), pyrazole (0.58 g,8.5 mmol), and cesium carbonate (2.8 g, 8.5 mmol) in 4 mL ofN-methylpyrrolidinone was heated to 100° C. for 17 h. After cooling tort, the mixture was diluted with water (75 mL) and extracted with ethylacetate (3×75 mL) and the combined extracts were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated invacuo to afford 1.7 g (71%) of 110A as a dark red oil. LCMS(M+H⁺)=190.1. HPLC Ret. time: 2.42 min.

Step B:

A mixture of 110A (0.95 g, 5.0 mmol) and 10% palladium on charcoal (0.27g) in 10 mL of ethyl acetate was stirred at rt under an atmosphere ofhydrogen for 17 h. The resulting mixture was filtered through a pad ofcelite and the resulting filtrate was concentrated in vacuo to afford0.73 g (91%) of 110B as a pale yellow oil. LCMS (M+H⁺)=160.1. HPLC Ret.time: 0.74 min.

Step C: Title Compound

The title compound was prepared as described for the preparation ofExample 97 by substituting 97B with 110B in Step D. LCMS (M+H⁺)=495.3.HPLC Ret. time: 2.91 min.

EXAMPLE 111

The title compound was prepared as described for the preparation ofExample 97. LCMS (M+H⁺)=539.3. HPLC Ret. time: 2.97 min.

EXAMPLE 112

Step A:

A mixture of 3-bromonitrobenzene (1.0 g, 5.0 mmol), imidazole (0.51 g,7.5 mmol), 1,10-phenanthroline (0.89 g, 5.0 mmol), dibenzylideneacetone(0.06 g, 0.25 mmol), cesium carbonate (1.8 g, 5.5 mmol), and copper(II)triflate benzene adduct (0.12 g, 0.25 mmol) in 1 mL of xylenes washeated at 120° C. for 36 h. After cooling to rt, the mixture was dilutedwith dichloromethane (100 mL) and washed with saturated aqueous ammoniumchloride solution (2×50 mL) and 1 N aqueous HCl (2×75 mL). The combinedacidic aqueous portions were neutralized to pH˜7 by adding 3N aqueousKOH and then extracted with dichloromethane (3×40 mL). The organicextracts were washed with brine (30 ml), dried over anhyd. sodiumsulfate, filtered, and concentrated in vacuo to afford 0.55 g (58%) of112A as a dark red semi-solid. LCMS (M+H⁺)=190.1. HPLC Ret. time: 0.44min.

Step B:

A mixture of 112A (0.55 g, 2.9 mmol) and 10% palladium on charcoal (0.15g) in 15 mL of methanol was stirred at rt under an atmosphere ofhydrogen for 17 h. The resulting mixture was filtered through a pad ofcelite and the resulting filtrate was concentrated in vacuo to afford0.36 g (77%) of 112B as a pale yellow solid. LCMS (M+H⁺)=160.1. HPLCRet. time: 0.19 min.

Step C: Title Compound

The title compound was prepared as described for the preparation ofExample 97 by substituting 97B with 112B in Step D. LCMS (M+H⁺)=495.2.HPLC Ret. time: 2.12 min.

EXAMPLE 113

The title compound was prepared as described for the preparation ofExample 97. LCMS (M+H⁺)=539.3. HPLC Ret. time: 2.32 min.

EXAMPLE 114

Step A:

To a mixture of 3-bromonitrobenzene (1.0 g, 5.0 mmol), 2-pyrrolidinone(0.50 g, 5.9 mmol), potassium carbonate (1.37 g, 9.9 mmol), andtrans-1,2-cyclohexanediamine (0.06 mL, 0.50 mmol) were successivelyadded 2.5 mL of anhydrous 1,4-dioxane and copper (I) iodide (94 mg, 0.50mmol) and the contents were heated to 110° C. for 24 h. After cooling tort, the mixture was partitioned between water (50 mL) and ethyl acetate(75 mL). The aqueous layer was extracted with additional ethyl acetate(2×50 mL) and the combined extracts were washed with brine (30 ml),dried over anhyd. sodium sulfate, filtered, and concentrated in vacuo toafford the crude product as a dark brown solid. Purification by flashchromatography on silica gel using a gradient elution from 70% ethylacetate in hexanes to 100% ethyl acetate gave 0.68 g (68%) of 114A as apale yellow solid after concentration in vacuo. LCMS (M+H⁺)=208.1. HPLCRet. time: 2.11 min.

Step B:

A mixture of 114A (0.68 g, 3.3 mmol) and 10% palladium on charcoal (0.35g) in 10 mL of methanol was stirred at rt under an atmosphere ofhydrogen for 17 h. The resulting mixture was filtered through a pad ofcelite and the resulting filtrate was concentrated in vacuo to afford0.55 g (95%) of 114B as an off-white solid. LCMS (M+H⁺)=177.1. HPLC Ret.time: 0.34 min.

Step C: Title Compound

The title compound was prepared as described for the preparation ofExample 97 by substituting 97B with 114B in Step D. LCMS (M+H⁺)=512.2.HPLC Ret. time: 2.68 min.

EXAMPLE 115

The title compound was prepared as described for the preparation ofExample 97. LCMS (M+H⁺)=556.3. HPLC Ret. time: 2.77 min.

EXAMPLE 116

Step A:

To a solution of 4-methyl-3-nitroaniline (3.93 g, 25.8 mmol) in 200 mLof dichloromethane at rt under argon was added2-chloropyridine-4-carbonyl chloride (5.00 g, 28.4 mmol) followed bytriethylamine (8.0 mL, 56.7 mmol) via syringe and the resulting mixturewas stirred for 2 h. The solvent removed in vacuo and the residue wastriturated with 20 mL of dichloromethane and the solid was collected byfiltration to yield 7.50 g (99.6%) of 116A as a yellow solid. HPLC Ret.Time: 3.13 min. MH⁺ (m/z) 292.3.

Step B:

To 116A (7.50 g) was added 50 ml of morpholine and the mixture washeated to 100° C. under argon for 20 h then cooled to rt and slowlypoured into ice-water (600 mL) with stirring. This mixture was stirredat rt for 15 min and the resulting solid was collected by filtration anddried in vacuo to afford 5.50 g (62.5%) of 116B as a light yellow solid.HPLC Ret. Time: 2.39 min. MH⁺ (m/z) 343.4.

Step C:

To compound 116B (1.50 g) in absolute ethanol (100 mL) was added 10%palladium on carbon (200 mg) and the mixture was shaken under hydrogen(30 psi) for 6 h. The solution was filtered through a pad of celite andthe solvent was removed in vacuo to give 1.33 g of 116C as a lightyellow solid. HPLC Ret. Time: 0.94 min. MH⁺ (m/z) 313.3.

Step D:

Compound 116C (0.20 g, 0.64 mmol) and4-chloro-5-methylpyrrolotriazine-6-ethylcarboxylate (0.14 g, 0.58 mmol)in anhydrous DMF was stirred at rt for 20 h. The reaction was dilutedwith ice-cold water and saturated aqueous sodium bicarbonate and theresulting precipitated solid was collected and washed with water to give0.30 g of 116D as a light yellow solid. HPLC Ret. Time: 2.96 min. MH⁺(m/z) 516.2.

Step E:

116D (0.30 g, 0.58 mmol) in 3 mL of 1N sodium hydroxide and 2 mL ofmethanol was heated at 60° C. for 4 h. Methanol was removed in vacuo andthe aqueous mixture was acidified with 1N aqueous HCl to pH˜2. Theresulting solid was collected and washed with water to give 0.24 g of116E as a pale yellow solid. HPLC Ret. time: 2.26 min. MH⁺ (m/z) 488.2.

Step F: Title Compound

116E (40 mg, 0.082 mmol), EDAC (19 mg, 0.098 mmol), HOBt (13 mg, 0.098mmol), and Hunig's base (43 μL, 0.25 mmol) were stirred at rt for 0.5 hand ethylamine hydrochloride (13 mg, 0.16 mmol) was added followed bystirring overnight. The crude reaction mixture was purified byreverse-phase preparative HPLC to give 28 mg of the title compound as awhite solid. HPLC Ret. time: 2.12 min. MH⁺ (m/z) 515.1.

EXAMPLE 117

The title compound was prepared from 116E as described in step F for thepreparation of Example 116. HPLC Ret. Time: 2.82 min. MH⁺ (m/z) 591.2.

EXAMPLE 118

The title compound was prepared from 116E as described in step F for thepreparation of Example 116. HPLC Ret. Time: 1.82 min. MH⁺ (m/z) 592.2.

EXAMPLE 119

Step A:

3-Fluorobenzonitrile (10.0 g, 82.6 mmol) and morpholine (40 mL, 0.45mol) in DMSO (70 mL) was heated at 100° C. for 3 days. The mixture wascooled to rt and poured into 500 mL of cold water. The resulting solidwas collected by filtration to give 9.52 g of 119A as a pink solid. HPLCRet. Time: 2.30 min. MH⁺ (m/z) 189.2.

Step B:

A mixture of 119A (9.50 g) in 6N aqueous sulfuric acid (80 mL) wasrefluxed for 20 h. After cooling to 0° C., the mixture was brought to apH of 2 by the slow addition of aqueous sodium hydroxide solution (50%w/w). After stirring for 15 min, the resulting solid was collected byfiltration and washed with water then triturated with ethyl acetate (600ml). The aqueous filtrate was extracted with additional ethyl acetate(450 ml) and the combined organic extracts were dried over anhydroussodium sulfate, filtered, and concentrated in vacuo to afford 9.50 g of119B as a light pink solid. HPLC Ret. Time: 1.94 min. MH⁺ (m/z) 208.1.

Step C:

To 119B (10.3 g, 50.0 mmol) in anhydrous dichloromethane (300 mL) at rtwas slowly added oxalyl chloride (5.2 mL, 60.0 mmol) followed by 1 dropof anhydrous DMF. The reaction was stirred at room temperature for 3 hand the solvent was removed in vacuo to afford an oil which wasdissolved in anhydrous dichloromethane (200 mL). To this solution wasadded 4-methyl-3-nitroaniline (50 mmol) followed by a slow addition oftriethylamine (20 mL, 140 mmol) and the mixture was stirred at rtovernight. The reaction was diluted with dichloromethane (400 mL) andwashed with water (150 mL×2), saturated aqueous sodium bicarbonate (150mL×2), then dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to afford the crude product which wasrecrystallized from ethyl acetate to give 9.57 g (56%) of 119C as ayellow solid. HPLC Ret. Time: 3.07 min. MH⁺ (m/z) 342.1.

Step D:

Compound 119D was prepared as described for compound 116C.

Step E:

119E was prepared from4-chloro-5-,methylpyrrolotriazine-6-ethylcarboxylate as described for116D by substituting compound 119D for compound 116C. HPLC Ret. Time:3.39 min. MH⁺ (m/z) 515.1.

Step F:

119F was prepared from 119E as described for 116E. HPLC Ret. Time: 2.78min. MH⁺ (m/z) 487.2.

Step G: Title Compound

The title compound was prepared from 119F as described in Step F for thepreparation of Example 116. HPLC Ret. Time: 2.68 min. MH⁺ (m/z) 514.1.

EXAMPLES 120 TO 123

Examples 120-123 were prepared as described for Example 119.

Ex. # Structure HPLC retention time (min) (M + H)+ 120

3.21 589.7 121

2.32 591.4 122

2.59 544.3 123

2.71 558.1

EXAMPLE 124

Step A:

Compound 124A was prepared from 4-methyl-3-nitroaniline utilizing thesame procedure used for compound 116A by substituting3,5-difluorobenzoyl chloride for 2-chloropyridine-4-carbonyl chloride.

Step B:

Compound 124A (12.2 g) in 80 mL of morpholine was refluxed under argonfor 3 days. The resulting mixture was cooled to rt and poured intoice-water (1000 mL) with stirring. The mixture was stirred at rt for 15min and the resulting solid was collected by filtration and dried invacuo to afford 14.6 g of 124B as a light yellow solid. HPLC Ret. Time:3.35 min. MH⁺ (m/z) 360.1.

Step C:

Compound 124C was prepared from by hydrogenation using Pd/C catalyst andhydrogen.

Step D:

124D was prepared from4-chloro-5-methylpyrrolotriazine-6-ethylcarboxylate as described for116D by substituting compound 124C for compound 116C. HPLC Ret. Time:3.59 min. MH⁺ (m/z) 533.3.

Step E:

124E was prepared from 124D as described for 116E. HPLC Ret. Time: 3.06min. MH⁺ (m/z) 505.0.

Step F: Title Compound

The title compound was prepared from 124E as described in Step F for thepreparation of Example 116. HPLC Ret. Time: 2.93 min. MH⁺ (m/z) 532.1.

EXAMPLES 125 TO 147

Examples 125-147 were prepared as described for Example 124.

Ex. # Structure HPLC retention time (min) (M + H)+ 125

2.94 544.3 126

2.64 548.3 127

2.68 504.2 128

3.43 608.4 129

2.99 576.2 130

2.57 609.4 131

2.77 518.3 132

2.78 532.4 133

2.96 544.3 134

3.10 546.3 135

3.06 546.3 136

2.64 548.3 137

3.22 560.3 138

3.28 560.4 139

2.87 562.4 140

2.86 562.0 141

2.78 574.4 142

2.34 575.4 143

2.97 576.3 144

3.40 608.4 145

2.47 615.4 146

2.36 617.3 147

2.68 504.2

EXAMPLE 148

Step A:

148A was prepared from4-chloro-5-methylpyrrolotriazine-6-ethylcarboxylate as described for116D by substituting 2-methyl-5-nitroaniline for compound 116C. HPLCRet. Time: 3.55 min. MH⁺ (m/z) 356.3.

Step B:

148B was prepared from 148A as described for 116E. HPLC Ret. Time: 2.89min. MH⁺ (m/z) 328.1.

Step C:

Compound 148C was prepared from 148B as described in Step F for thepreparation of Example 116 by substituting ethylamine hydrochloride with(S)-(α)-(−)-methylbenzylamine. HPLC Ret. Time: 3.32 min. MH⁺ (m/z)431.2.

Step D:

Compound 148D was prepared by hydrogenation using Pd/C catalyst andhydrogen. HPLC Ret. Time: 2.37 min. MH⁺ (m/z) 401.3.

Step E: Title Compound

To a rt solution of 148D (30 mg, 0.075 mmol) in anhydrous DMF (0.3 mL)were successively added triethylamine (0.14 mmol) and 2-methyl benzoylchloride (0.11 mmol) and the resulting mixture was stirred overnight.The crude reaction mixture was subjected to purification byreverse-phase preparative HPLC to afford the title compound. HPLC Ret.Time: 3.37 min. MH⁺ (m/z) 519.2.

EXAMPLES 149 TO 206

The following compounds were prepared as described for the preparationof Example 148 by substituting (S)-(α)-(−)-methylbenzylamine in Step Cwith the appropriate amine and by substituting 2-methyl benzoyl chloridein Step E with the appropriate acid chloride.

Ex. # Structure HPLC retention time (min) (M + H)+ 149

2.67 498.4 150

3.20 541.4 151

2.33 426.3 152

2.26 500.4 153

3.37 523.3 154

3.20 530.2 155

3.29 535.3 156

3.51 539.2 157

3.57 573.2  3.57 158

3.63 589.2 159

3.36 519.3 160

3.24 530.1 161

3.20 535.2 162

3.28 541.2 163

3.41 565.3 164

3.84 573.2 165

3.93 641.2 166

3.27 573.2 167

3.18 505.2 168

2.77 506.3 169

3.26 548.3 170

2.05 411.2 171

2.39 439.5 172

2.68 465.4 173

2.65 473.2 174

2.11 474.4 175

2.51 492.4 176

2.70 498.4 177

2.70 498.4 178

2.71 517.3 179

2.67 533.4 180

3.20 541.4 181

3.28 557.4 182

2.50 475.2 183

2.06 513.4 184

2.73 515.2 185

2.83 483.0 186

3.23 559.0 187

2.89 527.0 188

2.77 491.4 189

2.95 509.2 190

3.31 559.3 191

2.43 551.3 192

2.95 576.3 193

2.57 454.2 194

2.78 468.3 195

2.52 484.4 196

2.31 470.1 197

2.74 495.2 198

2.72 524.2 199

2.00 527.4 200

2.01 557.4 201

1.98 495.4 202

1.95 525.3 203

2.54 512.3 204

2.51 542.4 205

2.04 513.3 206

2.03 543.3

EXAMPLE 207

Step A:

A suspension of chloropyrrolotriazine (2.03 g, 8.47 mmol) and3-nitro-5-methyl aniline (1.41 g, 9.3 mmol) in DMF (25 mL) was stirredat rt for 24 h. Water (125 mL) was added over 30 min and the solutionstirred for 1 h upon which the pH was adjusted to neutral with sat. aq.NaHCO₃. The solids were filtered, washed with water, and dried to givecompound A (2.589 g, 85% yield) as a pale tan solid.

Step B:

To a solution of Compound A (825 mg, 2.32 mmol) in THF (2 mL) and MeOH(1 mL) was added 1N NaOH (6 mL) and the reaction heated at 60° C. for 24h. The reaction mixture was cooled, concentrated to remove the organicsolvents, and the pH was adjusted to neutral with 1 N HCl. The solidswere filtered, washed with water, and dried to give compound B. LCMS(M+H⁺)=328.1. HPLC (Condition A): 3.40 min.

Step C:

A solution of compound B (2.32 mmol), EDCI (489 mg, 2.55 mmol), and HOBt(345 mg, 2.55 mmol) in DMF (6 mL) was stirred at rt for 1 h, and thenn-propyl amine (0.38 mL, 6.4 mmol) was added. The reaction was stirredfor 4 h and water was added to precipitate the product. The solids werefiltered and purified via column chromatography on silica (33% ethylacetatehexanes) to give compound C (0.79 g, 93% yield) as a white solid.¹H NMR (CDCl₃): δ 9.11 ( s, 1H), 7.92 (m, 2H), 7.71 (s, 1H), 7.36 (d,J=8.4 Hz, 1H), 5.82 (br m, 1H), 3.34 (q, J=6.7 Hz, 2H), 2.86 (s, 3H),2.41 (s, 3H), 1.58 (m, 2H), 1.16 (t, J=7.5 Hz, 3H). LCMS (M+H⁺)=369.3.HPLC (Condition A): 3.42 min.

Step D:

A solution of compound C (794 mg, 2.16 mmol) and 10% Pd/C (250 mg, wet)in MeOH (20 mL) was degassed and backfilled with hydrogen three timesand stirred for 2 h. The solution was filtered and concentrated to givecompound D (691 mg, 95% yield). ¹H NMR (CDCl₃): δ7.94 (s, 1H), 7.73 (s,1H), 7.53 (s, 1H), 7.23 (m, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.53 (dd,J=8.1, 2.2 Hz, 1H) 5.86 (br m, 1H), 3.43 (q, J=6.6 Hz, 2H), 2.91 (s,3H), 2.27 (s, 3H), 1.68 (m, 2H), 1.02 (t, J=7.1 Hz, 3H). LCMS(M+H⁺)=339.2. HPLC (Condition A): 2.39 min.

Step E: Title Compound

To a suspension of 2.5 g (7.4 mmol) of compound D in 50 mL of CH₂Cl₂ wasadded 1.42 μL of DIPEA at rt. The reaction mixture was cooled to 0° C.and added ethylchloroformate (0.77 mL). The reaction was stirred for 2 hat room temperature and then quenched with MeoH. The solvents wereremoved and the product precipitated with water (40 mL). The product wascollected by vacuum filtration and washed with water (2×) then dissolvedin hot MeOH, decolorized with charcoal and recrystallized from EtOH togive 2.10 g (70%) of the titled compound as a pure product.

EXAMPLES 208 TO 233

Compounds having the formula below, wherein W and B^(a) have the valueslisted in the Table provided below, were prepared following the sameprocedure described for Example 1, using the appropriate acid chloride,chloroformate or isocyanate.

HPLC ret. time Ex. No. W B^(a) (min.) MS (M + H)+ 208 —NHCH₂CH₃ —CH₃2.41 367.2 209 —NHCH₂CH₂CH₃ —CH₃ 2.74 381.4 210 —NHCH₂CH₃ —CH₂CH₃ 2.85381.2 211 —NHCH₂CH₂CH₃ —CH₂CH₃ 2.85 395.2 212 —OCH₃ —OCH₂CH₃ 3.51 384.2213 —NHCH₂CH₂CH₃ —OCH₂CH₃ 3.16 411.2 214

—OCH₂CH₃ 3.00 441.3 215

—OCH₂CH₃ 3.29 425.3 216 —NHCH₂CH₃ —OCH₂CH₃ 2.89 397.3 217 —NHCH(CH₃)₂—OCH₂CH₃ 3.10 411.2 218 —NHCH₂CH₂OH —OCH₂CH₃ 2.54 413.2 219 —NHCH₂CH₂CH₃—OCH₃ 2.94 397.2 220 —NHCH₂CH₂CH₃ —OCH₂CH₂CH₃ 3.03 425.2 221—NHCH₂CH₂CH₃ —OCH(CH₃)₂ 3.38 425.3 222 —NHCH₂CH₂CH₃ —OCH₂CH₂F 3.00 429.2223 —NHCH₂CH₂CH₃

3.38 459.2 224 —NHCH₂CH₂CH₃

3.72 473.3 225 —NHCH₂CH₃ —CH₂OCH₃ 2.39 381.2 226 —NHCH₂CH₂CH₃ —CH₂OCH₃2.83 411.2 227 —NHCH₂CH₂CH₃

3.86 503.5 228 —OCH₃

2.46 491.2 229

3.46 584.4 230 —NHCH₂CH₃

3.38 504.3 231 —NHCH₂CH₂CH₃

3.56 518.3 232

3.67 532.3 233 —NHCH(CH₃)₂

3.53 518.4

EXAMPLE 234

Step A:

p-Tolyl acetic acid (0.6 g, 4.1 mmol) was added H₂SO₄ (5.5 mL) withcooling in an ice bath. NaNO₃ (0.35 g, 4.1 mmol) was added slowly andmixture was stirred at 0-5° C. for 8 h. The solution was carefullypoured onto ice and the solids filtered and washed with water to give3-nitro p-tolylacetic acid (0.59 g, 74%).

The crude solid (160 mg) was hydrogenated under H₂ balloon in MeOH (15mL) in the presence of 10% Pd-C at rt for 2 h. Filtration gave 3-aminop-tolylacetic acid as a yellow solid (131 mg, 97%).

Step B:

3-Amino p-tolylacetic acid (131 mg, 0.8 mmol) and 1B (220 mg, 0.92 mmol)were stirred for 18 h in DMF (2 mL). Water was added to precipitate theproduct and the pH was adjusted to 6 with aq NaHCO₃. The solids werefiltered, washed with water and dried to afford the above ester (62%).

Step C: Title Compound

To the above acid (86 mg, 0.23 mmol) in DMF (2 mL) was added EDC (49 mg,0.26 mmol) and HOBt (35 mg, 0.26 mmol). The mixture was stirred for 1 hfollowed by addition of methylamine (0.25 ml, 2M in THF). The reactionwas stirred for 18 h then added water (12 mL). The solids-were filteredto obtain the title compound (75 mg, 84%). (M+H)+: 395.2, HPLC retentiontime: 2.85 min.

EXAMPLES 235 AND 236

Examples 235 and 236 were prepared from Example 234 following theprocedure described in Example 2 and 3.

Ex. HPLC ret. No. R4 J time (min.) MS (M + H)+ 235 —NHCH₂CH₂CH₃ —NHCH₃395.1 2.67 236 —NHCH₂CH₃ —NHCH₃ 381.2 2.39

EXAMPLE 237

Step A:

Compound 1B was hydrolyzed under standard saponification methods andcoupled with n-propylamine using the EDC/HOBt method to furnish the C-6n-propylamido oxopyrrolotriazine. A solution of this compound (1.65 g, 7mmol) in toluene (50 mL) was added POCl₃ (0.8 mL, 8.45 mmol) and DIPEA(1 mL, 5.6 mmol) and the solution heated at reflux for 10 h. Thereaction was cooled and poured into ice cold aqueous NaHCO₃. Thesolution was extracted with EtOAc (3×), dried over Na₂SO₄, filtered andconcentrated to give the chloride as a yellow solid (1.65 g, 93%) whichwas used without further purification.

Step B:

A solution of 3-nitro-4-methyl benzamide (402 mg, 2.2 mmol) indichloroethane (15 mL) was added propionic anhydride (2.45 mmol) andDMAP (381 mg, 3.1 mmol) and the reaction mixture heated at 55° C.Additional propionic anhydride (2.45 mmol) and DMAP (1.4 eq) was addedand the reaction temperature increased to 85° C. for 2 h. The reactionvessel was cooled and poured into CH₂Cl₂ (50 mL) and water (25 mL). Theorganic layer was washed with 1N HCl and brine, dried over Na₂SO₄,filtered and concentrated in vacuo to an oil which was purified viacolumn chromatography (15% then 30% EtOAc/hexane) to give the nitroimide (333 mg, 63%).

The above compound (152 mg, 0.6 mmol) was dissolved in EtOH (6 mL) andadded 5% Pd-C (wet, 35 mg) and evacuated and back filled under ahydrogen balloon. The reaction was stirred for 2 h, filtered andconcentrated to a white solid which was used without furtherpurification (132 mg, 99%).

The above aniline (20 mg) and chloride (20 mg) were combined in DMF(0.25 mL) and stirred for 18 h. The solution was added water (1 mL) dropwise and neutralized with dilute aq. NaHCO₃. The solids were stirredrapidly for 2 h then filtered and washed with water to give 33.6 mg, 98%yield.

EXAMPLE 238

Step A:

3-nitro-4-methyl benzamide (0.2 g, 1.1 mmol) was suspended indichloroethane (6 mL) and added oxalyl chloride (0.12 mL, 1.3 mmol) at0° C. The solution was allowed to warm to room temperature and stir for1 h followed by heating at reflux for 18 h. The reaction was cooled,concentrated to remove volatiles and dried under vacuum to give thedesired product which was used without further purification.

Step B:

To the crude acyl isocyanate was added CH₂Cl₂ (5 mL) and dry EtOH (1 mL)and the reaction stirred for 1 h. The solvents were removed in vacuo andthe solids filtered with EtOAc and washed with ether to give a whitesolid (203 mg, 73%). The crude solids were dissolved in MeOH (25 mL) andhydrogenated under hydrogen balloon in the presence of 5% Pd-C for 2 hto give a white solid after filtration (174 mg, 97%).

Step C: Title Compound

This solid from the previous step was coupled with the abovepyrrolotriazine chloride under standard conditions to afford the titlecompound in 55% yield.

EXAMPLES 239 TO 267

Examples 239-267 were prepared as described in Example 238 by reactingthe acyl isocyanate with an appropriate amine.

HPLC ret. time Ex. No. W J (min.) MS (M + H)+ 239 —NHCH₂CH₂CH₃ —OCH₃425.5 2.98 240 —NHCH₂CH₂CH₃ —OCH₂CH₃ 439.3 3.12 241 —NHCH₂CH₂CH₃—OCH(CH₃)₂ 435.4 3.30 242 —NHCH₂CH₂CH₃

487.6 3.53 243 —NHCH₂CH₃ —OCH₃ 411.2 2.66 244 —NHCH₂CH₃ —OCH₂CH₃ 425.32.86 245 —NHCH₂CH₃ —OCH(CH₃)₂ 439.3 3.09 246 —NHCH₂CH₃

473.5 3.32 247 —NHCH₃ —OCH₃ 397.2 2.47 248 —NHCH₃ —OCH₂CH₃ 411.2 2.67249 —NHCH₃ —OCH(CH₃)₂ 425.3 2.93 250 —NHCH₃

459.2 3.11 251 —NHCH(CH₃)₂ —OCH₃ 425.3 2.87 252 —NHCH(CH₃)₂ —OCH₂CH₃439.4 3.07 253 —NHCH(CH₃)₂ —OCH(CH₃)₂ 453.4 3.27 254 —NHCH(CH₃)₂

487.4 3.42 255 —NHCH₃ —NHCH₃ 396.0 2.68 256 —NHCH₃

422.0 3.09 257 —NHCH₂CH₃

436.3 3.26 258 —NHCH₂CH₂CH₃

450.4 3.49 259 —NHCH₂CH₂CH₃ —NHCH₃ 424.2 3.16 260 —OCH₂CH₃ —CH₃ 396.33.63 261 —OCH₂CH₃ —OCH₃ 412.2 3.56 262 —NHCH₂CH₂CH₃ —CH₃ 409.2 2.99 263—NHCH₂CH₂CH₃ —CH(CH₃)₂ 437.3 3.31 264 —NHCH₂CH₂CH₃ —CH₂CH₃ 423.2 3.16265 —NHCH₂CH₂CH₃

435.3 3.18 266 —NHCH₂CH₃

421.3 2.92 267 —NHCH₂CH₃ —CH₂CH₃ 409.3 2.95

EXAMPLES 268 TO 284

Step A:

A solution of 4-methyl-3-nitrobenzyl chloride (1.09 g, 5.87 mmol) in DMF(10 mL) was added phthalimide (0.86 g, 5.87 mmol), Bu4NI (50 mg) andK₂CO₃ (0.97 g) and the reaction mixture stirred rapidly for 4 h. Water(40 mL) was added dropwise and the slurry was stirred for 15 min. Thesolids were filtered and washed with water to give the protected amine(1.68 g, 97%).

The above solids (0.75 g) was suspended in EtOH (25 mL) and addedhydrazine (0.39 mL). The reaction mixture was heated to 60° C. for 8 hthen cooled. MeOH (25 mL) was added and the suspension stirred rapidlyto break up the solids. The product was filtered and rinsed with MeOH(2×) to give the product (0.38 g, 90%).

Step B:

The amine (0.38 g, 2.3 mmol) was dissolved in CH₂Cl₂ (10 mL) and cooledto 0° C. and added DIPEA (0.44 mL, 2.5 mmol). Ethyl chloroformate (0.22mL, 2.3 mmol) was added and the reaction stirred for 5 minutes followedby the addition of MeOH (0.1 mL). The mixture was concentrated to an oiland dissolved in EtOAc (30 mL) followed by washing with water, dilute aqNaHCO₃ and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated to an oil. Purification via column chromatography (25%EtOAc/hexane) afforded thejnitro product (500 mg, 92%).

The above product was dissolved in EtOH (5 mL) and EtOAc (5 mL) andadded 5% Pd-C (wet) followed by evacuation and backfilling with hydrogen(3×). The mixture was stirred for 1 h and filtered to give the product(177 mg, 99%).

This amine was then coupled and elaborated in a similar fashion asoutlined in Example 1 to give the examples in the Table provided below.

HPLC ret. time Ex. No. W J (min.) MS (M + H)+ 268 —OCH₂CH₃ —OCH₂CH₃ 3.75412.3 269 —OCH₂CH₃

3.88 444.2 270 —OCH₂CH₃ —CH₃ 3.41 382.3 271 —OCH₂CH₃ —CH₂OCH₃ 3.51 412.4272 —OCH₂CH₃ —CH₂CH₃ 3.53 396.4 273 —OCH₂CH₃

3.82 469.3 274 —NHCH₂CH₃

3.08 444.3 275 —NHCH₂CH₂CH₃

3.32 458.5 276 —NHCH₂CH₂OH

2.80 459.2 277 —NHCH₂CH₃ —CH₂OCH₃ 2.52 411.2 278 —NHCH₂CH₂CH₃ —CH₂OCH₃2.81 425.2 279 —NHCH₂CH₂OH —CH₂OCH₃ 2.15 427.1 280 —NHCH₂CH₃ —CH₂CH₃2.57 395.5 281 —NHCH₂CH₂CH₃ —CH₂CH₃ 2.88 409.2 282 —NHCH₂CH₂OH —CH₂CH₃2.21 411.5 283 —NHCH₂CH₃ —OCH₂CH₃ 2.90 411.3 284 —NHCH₂CH₂CH₃ —OCH₂CH₃3.15 425.3

EXAMPLES 285 TO 290

The following compounds were prepared according to the procedureoutlined in Example 31.

HPLC ret. time Ex. No. W J (min.) MS (M + H)+ 285 —NHCH₂CH₃ —NHNHCOH2.26 396.3 286 —NHCH₂CH₃

2.71 472.4 287 —NHCH₂CH₃

2.53 440.3 288 —NHCH₂CH₃

3.17 471.2 289 —NHCH₂CH₃

2.21 410.2 290 —NHCH₂CH₂CH₃ —NH₂ 2.68 367.3

EXAMPLES 291 TO 293

Step A:

A solution of 3-nitro-4-methylacetophenone (0.4 g, 2.23 mmol) in EtOH(12 mL) was added 5% Pd-C (wet, 100 mg). The flask was evacuated andbackfilled under hydrogen balloon (3×). The reaction was stirred for 3h, filtered and concentrated to give 3-amino-4-methylacetophenone (330mg, 99%).

Step B:

3-amino-4-methylacetophenone was then coupled with 1 B as in Example 1and elaborated to the C-6 amide in an identical fashion as in Example 2and 3 to produce the compounds listed in the below Table.

HPLC ret. time Ex. No. W J (min.) MS (M + H)+ 291 —OCH₂CH₃ —CH₃ 3.75353.3 292 —NHCH₂CH₃ —CH₃ 2.84 352.3 293 —NHCH₂CH₂CH₃ —CH₃ 3.08 366.4

EXAMPLE 294

Step A:

A solution of 3-nitro-4-methylacetophenone (0.1 g, 0.53 mmol) in MeOH (5mL) was added Accufluor and the solution heated at reflux for 18 h. Thereaction was cooled, concentrated and suspended in CH₂Cl₂. The solutionwas filtered and the organic filtrates were washed with sat. NaHCO₃ andwater. The organic layer was dried over Na₂SO₄, filtered andconcentrated to an oil which was purified via column chromatography (10%the 25% EtOAc/hexane) to furnish the above product (70 mg, 54%).

Step B: Title Compound

This product was reduced to the amine in an identical fashion as theabove examples to furnish 60 mg (98%) which was coupled directly withthe intermediate obtained in Step A in the preparation of Example 237,to afford 73 mg of the crude ketal which was treated with 3N HCl (0.1mL) in acetone (3 mL) for 2 d. The reaction was neutralized with sat aq.NaHCO₃ and diluted with water (3 mL). The solids were filtered to give55.3 mg of the title compoung.

EXAMPLE 295

Step A:

A solution of 3-nitro-4-methylbenzoyl chloride (1.6 g) in THF (50 mL)and MeCN (50 mL) was added trimethylsilyldiazomethane (5 mL, 2M inhexanes) and TEA (1.4 mL) at 0° C. The reaction mixture was stirred at0° C. for 24 h. The volatiles were removed in vacuo to give 3.3 g of acrude yellow solid. A portion was purified via column chromatography(25% EtOAc/hexane).

The above diazoketone (44 mg, 0.22 mmol) was dissolved in CH₂Cl₂ (1 mL)and EtOH (0.09 mL) and added BF₃OEt₂ (0.006 mL) was added. The mixturewas stirred for 90 min and a second addition of BF₃OEt₂ (0.005 mL) wasmade. The reaction mixture was stirred for 16 h and purified directlythrough a silica gel plug to afford the ketone (42.1 mg, 88%).

Step B:

The ketone was reduced to the amino-alcohol in an identical fashion asthe above examples and coupled to the chloropyrrolotriazine as inExample 1 to give the alcohol (58 mg).

Step C: Title Compound

The alcohol (56 mg, 0.14 mmol) was dissolved in CH₂Cl₂ and added PCC(36.3 mg, 0.17 mmol). The reaction was stirred at rt for 24 h, filteredthrough celite and purified via column chroamtography (25% EtOAc/hexane)to give the ketone (44 mg, 79%).

EXAMPLES 296 TO 305

Examples 296-305 were prepared according to the procedure outlined inExample 31.

Ex. Structure MW HPLC ret. t (min) MS (MH+) 296

404.43 2.96 405.2 297

390.4 2.56 391.2 298

417.47 2.37 418.3 299

431.5 2.6 432.3 300

493.57 3.07 494.3 301

432.49 3.17 433.2 302

418.46 2.75 419.3 303

521.63 3.22 522.2 304

459.56 2.84 460.3 305

445.53 2.62 446.4

EXAMPLES 306 AND 307

Examples 306-307 were prepared following the same procedure describedfor Example 3.

Ex. Structure MW HPLC ret. t (min) MS (MH+) 306

466.6 3.09 467 307

416.5 2.40 417

EXAMPLES 308 TO 311

Examples 308-311 were prepared following procedures similar to thatdescribed in Example 48.

Ex. Structure MW HPLC ret. T (min) MS (MH+) 308

389.5 2.63 390 309

387.4 3.00 388 310

373.4 2.89 374 311

391.5 3.15 392

1. A compound having the formula (I*):

or a pharmaceutically acceptable salt thereof, or an enantiomer thereof,or a diastereomer thereof, wherein X is selected from the groupconsisting of —O—, —OC(═O)—, —S—, —S(═O)—, —SO₂—, —C(═O)—, —CO₂—, —NR₈—,—NR₈C(═O)—, —NR₈C(═O)NR₉—, —NR₈CO₂—, —NR₈SO₂—, —NR₈SO₂NR₉—, —SO₂NR₈—,—C(═O)NR₈—, halogen, nitro, and cyano, or X is absent; Y—B is Z and iseither (a) —NR_(10a)CO—B^(a) or (b) —NR₁₀CO₂—B^(aa); B^(a) and B^(aa)are each independently selected from the group consisting of aC₃₋₇cycloalkyl which is optionally substituted with one to two of R₇, afive membered heteroaryl optionally substituted with one to two of R₇,and a five or six membered heterocyclo optionally substituted with oneto two of R₇; wherein: (a) R₇ is attached to any available carbon ornitrogen atom of B^(a) or B^(aa) when B^(a) or B^(aa) is a substitutedcycloalkyl, a substituted heterocyclo or a substituted heteroaryl, and(b) at each occurrence R₇ is independently selected from the groupconsisting of keto (═O), alkyl, substituted alkyl, halogen, haloalkoxy,ureido, cyano, —SR₂₀, —OR₂₀, —NR₂₀R₂₁, —NR₂₀SO₂R₂₁, —SO₂R₁₉,—SO₂NR₂₀R₂₁, —CO₂R₂₀, —C(═O)R₂₀, —C(═O)NR₂₀R₂₁, —OC(═O)R₂₀,—OC(═O)NR₂₀R₂₁, —NR₂₀C(═O)R₂₁, —NR₂₀CO₂R₂₁, aryl, cycloalkyl,heterocycle, and heteroaryl; and/or (c) when B^(a) or B^(aa) iscycloalkyl, two R₇ groups may join to form an optionally-substitutedcarbon-carbon bridge of three to four carbon atoms, or two R₇ groups mayjoin to form a fused carbocyclic, heterocyclic or heteroaryl ring, saidfused ring being in turn optionally substituted with one to three ofR₂₂; R₁ and R₅ are each independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, —OR₁₄, —SR₁₄, —OC(═O)R₁₄,—CO₂R₁₄, —C(═O)NR₁₄R_(14a), —NR₁₄R_(14a), —S(═O)R₁₄, —SO₂R₁₄,—SO₂NR₁₄R_(14a), —NR₁₄SO₂NR_(14a)R_(14b), —NR_(14a)SO₂R₁₄,—NR₁₄C(═O)R_(14a), —NR₁₄CO₂R_(14a), —NR₁₄C(═O)NR_(14a)R_(14b), halogen,nitro, and cyano; R₂ is hydrogen or C₁₋₄alkyl; R₃ is hydrogen, methyl,perfluoromethyl, methoxy, halogen, cyano, NH₂, or NH(CH₃); R₄ isselected from the group consisting of: (a) hydrogen, provided that R₄ isnot hydrogen if X is —S(═O)—, —SO₂—, —NR₈CO₂—, or —NR₈SO₂—; (b) alkyl,alkenyl, and alkynyl any of which may be optionally independentlysubstituted with keto and/or one to four of R₁₇; (c) aryl and heteroaryleither of which may be optionally independently substituted with one tothree of R₁₆; (d) heterocyclo and cycloalkyl either of which may beoptionally independently substituted with keto and/or one to three ofR₁₆; provided that R₄ is absent if X is halogen, nitro, or cyano; R₆ isattached to any available carbon atom of the phenyl ring and at eachoccurrence is independently selected from the group consisting of alkyl,halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl,alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy,carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono,arylsulfonylamino, alkylsulfonylamino, —SO₂OH, alkysulfonyl, sulfonamido, phenyl, benzyl, aryloxy, and benzyloxy, wherein each R₆ group in turnmay optionally be further substituted by one to two of R₁₈ wherepossible; R₈ and R₉ are each independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl,heterocyclo, and heteroaryl; R₁₀ and R_(10a) are each independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, and aryl; R₁₄, R_(14a) and R_(14b) are each independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl, provided that whenR₁₄ is joined to a sulphonyl group in —S(═O)R₁₄, —SO₂R₁₄, or—NR_(14a)SO₂R₁₄, then R₁₄ is not hydrogen; R₁₆ is selected from thegroup consisting of alkyl, R₁₇ and C₁₋₄alkyl substituted with keto (═O)and/or one to three of R₁₇; R₁₇ is selected from the group consistingof: (a) halogen, haloalkyl, haloalkoxy, nitro, cyano, —SR₂₃, —OR₂₃,—NR₂₃R₂₄, —NR₂₃SO₂R₂₅, —SO₂R₂₅, —SO₂NR₂₃R₂₄, —CO₂R₂₃, —C(═O)R₂₃,—C(═O)NR₂₃R₂₄, —OC(═O)R₂₃, —OC(═O)NR₂₃R₂₄, —NR₂₃C(═O)R₂₄, and—NR₂₃CO₂R₂₄; (b) aryl and heteroaryl either of which may be optionallysubstituted with one to three of R₂₆; and (c) cycloalkyl and heterocyclooptionally substituted with keto(═O) and/or one to three of R₂₆; R₁₈ andR₂₆ are each independently selected from the group consisting ofC₁₋₆alkyl, C₂₋₆alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro,amino, C₁₋₄alkylamino, aminoC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄alkyl,alkoxy, C₁₋₄alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy; R₁₉ isC₁₋₄alkyl, phenyl, C₃₋₇cycloalkyl or five- to six-membered heterocycloor heteroaryl; R₂₀ and R₂₁ are selected from the group consisting ofhydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl,phenyl, aryl, C₃₋₇cycloalkyl, and five-to-six membered heterocyclo andheteroaryl; R₂₂ is selected from the group consisting of C₁₋₆alkyl,C₂₋₆alkenyl, halogen haloalkyl, haloalkoxy, cyano, nitro, amino,C₁₋₄alkylamino, aminoC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄alkyl, alkoxy,alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy; R₂₃ and R₂₄ areeach independently selected from the group consisting of hydrogen,alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl,cycloalkyl, heteroaryl, and heterocyclo; R₂₅ is selected from the groupconsisting of alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl andheterocyclo; and m is 1, 2 or
 3. 2. The compound according to claim 1,or a pharmaceutically-acceptable salt thereof, wherein: B^(a) is acycloalkyl, heteroaryl, or heterocyclo ring selected from the groupconsisting of:

wherein (a) E, G, J and K are selected from O, S, NH and CH₂, providedthat when q is 0, then J and K are not simultaneously selected from Oand S; and M is N or CH; and (b) each hydrogen atom of E, G, J, K and Mmay optionally be replaced with an R₇ group; R₇ is selected from thegroup consisting of C₁₋₆alkyl, substituted C₁₋₄alkyl, halogen,trifluoromethoxy, trifluoromethyl, hydroxy, —C₁₋₄alkoxy, —C(═O)alkyl,—OC(═O)alkyl, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, —CN, —CO₂alkyl, —CONH₂,—CONH(CH₃), —CON(CH₃)₂, phenyl, benzyl, C₃₋₇ cycloalkyl, and five-to-sixmembered heterocyclo and heteroaryl; n is 0, 1 or 2; and p and q areeach independently selected from 0, 1, 2, 3 and 4, provided that p and qtaken together are not greater than
 4. 3. The compound according toclaim 1 or a pharmaceutically acceptable salt thereof, in which R₁ andR₅ are independently hydrogen or CH₃.
 4. The compound according to claim1, or a pharmaceutically acceptable salt thereof, in which R₂ ishydrogen.
 5. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, in which R₃ is methyl, —CF₃, or —OCF₃.
 6. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, in which X is —C(═O)— or —C(═O)NH—.
 7. The compound accordingto claim 1, or a pharmaceutically acceptable salt thereof, in which X is—C(═O)NH— and R₄ is C₂₋₆alkyl, optionally-substituted benzyl, or aheterocycic or heteroaryl ring selected from diazepinyl, morpholinyl,piperidinyl, and pyrrolidinyl, said heterocycle being optionallysubstituted with one to two of C₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, phenyl,and/or benzyl.
 8. The compound according to claim 1, or apharmaceutically acceptable salt thereof, in which X is —C(═O)— and R₄is phenyl, pyridyl, pyrimidinyl, or pyrazinyl optionally-substitutedwith one to two of C₁₋₄alkyl, halogen, hydroxy, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl,phenyloxy, benzyloxy, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂ and/or aC₁₋₄alkyl substituted with one to two of halogen, hydroxy, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl,phenyloxy, benzyloxy, NH₂, NH(C₁₋₄alkyl), and/or N(C₁₋₄alkyl)₂.
 9. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof in which (a) B^(a) is cyclopropyl or cyclobutyl optionallysubstituted with one to two of R₇, or (b) B^(a) is selected from thegroup consisting of:

R₇ is selected from the group consisting C₁₋₄alkyl, trifluoromethyl,trifluoromethoxy, halogen, cyano, amino, C₁₋₄alkylalmino, hydroxy,C₁₋₄alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; and n is 0, 1 or2.
 10. A pharmaceutical composition comprising one or more of a compoundaccording to claim 1 and a pharmaceutically-acceptable carrier ordiluent.
 11. A method of treating an inflammatory disorder comprisingadministering to a patient in need of such treatment a pharmaceuticalcomposition according to claim 10, wherein the inflammatory disorder isselected from asthma, adult respiratory distress syndrome, chronicobstructive pulmonary disease, chronic pulmonary inflammatory disease,diabetes, inflammatory bowel disease, osteoporosis, psoriasis, graft vs.host rejection, atherosclerosis, multiple myeloma, myocardial ischemia,ischemia, rheumatoid arthritis, psoriatic arthritis, traumaticarthritis, rubella arthritis, gouty arthritis, or osteoarthritis.
 12. Acompound having the formula,

or a pharmaceutically acceptable salt thereof, or an enantiomer thereof,or a diastereomer thereof, wherein R₃ is methyl or CF₃; X is —C(═O)— or—C(═O)NH—; R₄ is straight or branched C₂₋₆alkyl; cycloalkyl optionallysubstituted with keto and/or up to two of R₁₆; heterocycle or heteroaryloptionally substituted with keto and/or up to two of R₁₆; C₁₋₄alkylsubstituted with up to three of halogen, trifluoromethyl, cyano,hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy orbenzyloxy, wherein said phenyl group is optionally substituted with oneto two of R₂₆; or phenyl optionally substituted with zero to two of R₁₆;R_(6a) is selected from the group consisting of lower alkyl, halogen,trifluoromethoxy, trifluoromethyl, hydroxy, C₁₋₄alkoxy, nitro, amino,C₁₋₄alkylamino, and cyano; B is cyclopropyl or cyclobutyl optionallysubstituted with one to two R₇; or B is selected from the groupconsisting of:

R₇ is C₁₋₄alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano,amino, C₁₋₄alkylalmino, hydroxy, C₁₋₄alkoxy, phenyl, benzyl, phenyloxy,or benzyloxy; n is 0, 1 or 2; R₁₆ at each occurrence is independentlyselected from the group consisting of hydrogen, alkyl, trifluoromethyl,trifluoromethoxy, halogen, cyano, nitro, amino, C₁₋₄alkylamino,aminoC₁₋₄alkyl, haloC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄alkyl, alkoxy,phenyl, benzyl, phenyloxy, and benzyloxy; and R₂₂ and R₂₆ are eachindependently selected from the group consisting of C₁₋₆alkyl,C₂₋₆alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino,C₁₋₄alkylamino, aminoC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄alkyl, alkoxy,alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy.
 13. A compoundhaving the formula,

or a pharmaceutically acceptable salt thereof, or an enantiomer thereof,or a diastereomer thereof, wherein R₃ is methyl or CF₃; X is —C(═O)— or—C(═O)NH—; R₄ is a straight or branched C₂₋₆alkyl; cycloalkyl optionallysubstituted with keto and/or up to two of R₁₆; heterocycle or heteroaryloptionally substituted with keto and/or up to two of R₁₆; C₁₋₄alkylsubstituted with up to three of halogen, trifluoromethyl, cyano,hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy orbenzyloxy, wherein said phenyl group is optionally substituted with oneto two of R₂₆; or phenyl optionally substituted with zero to two of R₁₆;R_(6a) is selected from lower alkyl, halogen, trifluoromethoxy,trifluoromethyl, hydroxy, C₁₋₄alkoxy, nitro, amino, C₁₋₄alkylamino, andcyano; B is cyclopropyl or cyclobutyl optionally substituted with one totwo of R₇; or B is selected from the group consisting of:

R₇ is C₁₋₄alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano,amino, C₁₋₄alkylalmino, hydroxy, C₁₋₄alkoxy, phenyl, benzyl, phenyloxy,or benzyloxy; n is 0, 1 or 2; R₁₆ at each occurrence is independentlyselected from the group consisting of hydrogen, alkyl, trifluoromethyl,trifluoromethoxy, halogen, cyano, nitro, amino, C₁₋₄alkylamino,aminoC₁₋₄alkyl, haloC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄alkyl, alkoxy,phenyl, benzyl, phenyloxy, and benzyloxy; and R₂₂ and R₂₆ are eachindependently selected from the group consisting of C₁₋₆alkyl,C₂₋₆alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino,C₁₋₄alkylamino, aminoC₁₋₄alkyl, hydroxy, hydroxyC₁₋₄alkyl, alkoxy,alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy.